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PubMed1991

Database of homology-derived protein structures and the structural meaning of sequence alignment.

The database of known protein three-dimensional structures can be significantly increased by the use of sequence homology, based on the following observations. (1) The database of known sequences, currently at more than 12,000 proteins, is two orders of magnitude larger than the database of known structures. (2) The currently most powerful method of predicting protein structures is model building by homology. (3) Structural homology can be inferred from the level of sequence similarity. (4) The threshold of sequence similarity sufficient for structural homology depends strongly on the length of the alignment. Here, we first quantify the relation between sequence similarity, structure similarity, and alignment length by an exhaustive survey of alignments between proteins of known structure and report a homology threshold curve as a function of alignment length. We then produce a database of homology-derived secondary structure of proteins (HSSP) by aligning to each protein of known structure all sequences deemed homologous on the basis of the threshold curve. For each known protein structure, the derived database contains the aligned sequences, secondary structure, sequence variability, and sequence profile. Tertiary structures of the aligned sequences are implied, but not modeled explicitly. The database effectively increases the number of known protein structures by a factor of five to more than 1800. The results may be useful in assessing the structural significance of matches in sequence database searches, in deriving preferences and patterns for structure prediction, in elucidating the structural role of conserved residues, and in modeling three-dimensional detail by homology.

Amino Acid Sequence↗
PubMedDate not supplied

[Analysis of structural motifs of proteins using sets of codes, describing local structures].

An amino acid sequence pattern conserved among a family of proteins is called motif. It is usually related to the specific function of the family. On the other hand, functions of proteins are achieved by their 3D structures. Specific local structures, called structural motifs, are considered related to their functions. However, searching for common structural motifs in different proteins is much more difficult than for common sequence motifs. We are attempting in this study to convert the information about the structural motifs into a set of one-dimensional digital strings, i.e., a set of codes, to compare them more easily by computer and to investigate their relationship to functions more quantitatively. By applying the Delaunay tessellation to a 3D structure of a protein, we can assign each local structure to a unique code that is defined so as to reflect its structural feature. Since a structural motif is defined as a set of the local structures in this paper, the structural motif is represented by a set of the codes. In order to examine the ability of the set of the codes to distinguish differences among the sets of local structures with a given PROSITE pattern that contain both true and false positives, we clustered them by introducing a similarity measure among the set of the codes. The obtained clustering shows a good agreement with other results by direct structural comparison methods such as a superposition method. The structural motifs in homologous proteins are also properly clustered according to their sources. These results suggest that the structural motifs can be well characterized by these sets of the codes, and that the method can be utilized in comparing structural motifs and relating them with function.

Amino Acid Motifs↗
PubMed1998

Solution structure and dynamics of linked cell attachment modules of mouse fibronectin containing the RGD and synergy regions: comparison with the human fibronectin crystal structure.

We report the three-dimensional solution structure of the mouse fibronectin cell attachment domain consisting of the linked ninth and tenth type III modules, mFnFn3(9,10). Because the tenth module contains the RGD cell attachment sequence while the ninth contains the synergy region, mFnFn3(9,10) has the cell attachment activity of intact fibronectin. Essentially complete signal assignments and approximately 1800 distance and angle restraints were derived from multidimensional heteronuclear NMR spectra. These restraints were used with a hybrid distance geometry/simulated annealing protocol to generate an ensemble of 20 NMR structures having no distance or angle violations greater than 0.3 A or 3 degrees. Although the beta-sheet core domains of the individual modules are well-ordered structures, having backbone atom rmsd values from the mean structure of 0.51(+/-0.12) and 0.40(+/-0.07) A, respectively, the rmsd of the core atom coordinates increases to 3.63(+/-1.41) A when the core domains of both modules are used to align the coordinates. The latter result is a consequence of the fact that the relative orientation of the two modules is not highly constrained by the NMR restraints. Hence, while structures of the beta-sheet core domains of the NMR structures are very similar to the core domains of the crystal structure of hFnFn3(9,10), the ensemble of NMR structures suggests that the two modules form a less extended and more flexible structure than the fully extended rod-like crystal structure. The radius of gyration, Rg, of mFnFn3(9,10) derived from small-angle neutron scattering measurements, 20.5(+/-0.5) A, agrees with the average Rg calculated for the NMR structures, 20.4 A, and is ca 1 A less than the value of Rg calculated for the X-ray structure. The values of the rotational anisotropy, D ||/D perpendicular, derived from an analysis of 15N relaxation data, range from 1.7 to 2.1, and are significantly less than the anisotropy of 2.67 predicted by hydrodynamic modeling of the crystal coordinates. In contrast, hydrodynamic modeling of the NMR coordinates yields anisotropies in the range of 1.9 to 2.7 (average 2.4(+/-0.2)), with NMR structures bent by more than 20 degrees relative the crystal structure having calculated anisotropies in best agreement with experiment. In addition, the relaxation parameters indicate that several loops in mFnFn3(9,10), including the RGD loop, are flexible on the nanosecond to picosecond time-scale. Taken together, our results suggest that, in solution, the limited set of interactions between the mFnFn3(9,10) modules position the RGD and synergy regions to interact specifically with cell surface integrins, and at the same time permit sufficient flexibility that allows mFnFn3(9,10) to adjust for some variation in integrin structure or environment.

Amino Acid Sequence↗
PubMed2000

Towards a complete description of the structural and dynamic properties of the denatured state of barnase and the role of residual structure in folding.

The detailed characterization of denatured proteins remains elusive due to their mobility and conformational heterogeneity. NMR studies are beginning to provide clues regarding residual structure in the denatured state but the resulting data are too sparse to be transformed into molecular models using conventional techniques. Molecular dynamics simulations can complement NMR by providing detailed structural information for components of the denatured ensemble. Here, we describe three independent 4 ns high-temperature molecular dynamics simulations of barnase in water. The simulated denatured state was conformationally heterogeneous with respect to the conformations populated both within a single simulation and between simulations. Nonetheless, there were some persistent interactions that occurred to varying degrees in all simulations and primarily involved the formation of fluid hydrophobic clusters with participating residues changing over time. The region of the beta(3-4) hairpin contained a particularly high degree of such side-chain interactions but it lacked beta-structure in two of the three denatured ensembles: beta(3-4) was the only portion of the beta-structure to contain significant residual structure in the denatured state. The two principal alpha-helices (alpha1 and alpha2) adopted dynamic helical structure. In addition, there were persistent contacts that pinched off core 2 from the body of the protein. The rest of the protein was unstructured, aside from transient and mostly local side-chain interactions. Overall, the simulated denatured state contains residual structure in the form of dynamic, fluctuating secondary structure in alpha1 and alpha2, as well as fluctuating tertiary contacts in the beta(3-4) region, and between alpha1 and beta(3-4), in agreement with previous NMR studies. Here, we also show that these regions containing residual structure display impaired mobility by both molecular dynamics and NMR relaxation experiments. The residual structure was important in decreasing the conformational states available to the chain and in repairing disrupted regions. For example, tertiary contacts between beta(3-4) and alpha1 assisted in the refolding of alpha1. This contact-assisted helix formation was confirmed in fragment simulations of beta(3-4) and alpha1 alone and complexed, and, as such, alpha1 and beta(3-4) appear to be folding initiation sites. The role of these sites in folding was investigated by working backwards and considering the simulation in reverse, noting that earlier time-points from the simulations provide models of the major intermediate and transition states in quantitative agreement with data from both unfolding and refolding experiments. Both beta(3-4) and alpha1 are dynamic in the denatured state but when they collide and make enough contacts, they provide a loose structural scaffold onto which further beta-strands pack. The beta-structure condenses about beta(3-4), while alpha1 aids in stabilizing beta(3-4) and maintaining its orientation. The resulting beta-structure is relatively planar and loose in the major intermediate. Further packing ensues, and as a result the beta-sheet twists, leading to the major transition state. The structure is still expanded and loops are not well formed at this point. Fine-tuning of the packing interactions and the final condensation of the structure then occurs to yield the native state.

Amino Acid Sequence↗
PubMed2003

Chains of [RE6] octahedra coupled by (NCN) links in the network structure of RE2Cl(CN2)N. Synthesis and structure of two novel rare earth chloride carbodiimide nitrides with structures related to the RE2Cl3 type.

Solid state metathesis reactions between RECl(3) (RE = La, Ce) and Li(2)CN(2) at 800 degrees C have led to the discovery of the rare earth chloride carbodiimide nitrides La(2)Cl(CN(2))N (1) and Ce(2)Cl(CN(2))N (2), respectively. Single crystal X-ray diffraction analyses revealed that 1 and 2 crystallize isotypic in an orthorhombic system (Cmmm, Z = 4, a = 13.3914(8) A, b = 9.6345(7) A, c = 3.9568(2) A for 1 and a = 13.340(1) A, b = 9.5267(8) A, c = 3.9402(5) A for 2). The crystal structures of 1 and 2 contain linear chains of edge-sharing octahedra built from rare earth metal atoms. Similar to [M(6)X(8)] type clusters, the [RE(6)] octahedra are capped by eight nitrogen atoms above their faces, of which four are from N(3-) ions and the other four are from (CN(2))(2-) ions. The chains are interconnected by bridging (CN(2))(2-) to form a three-dimensional network with Cl(-) ions in linear channels. Compounds 1 and 2 are surprisingly stable toward air and water. They have been characterized by thermal analysis, infrared spectroscopy, and magnetic susceptibility studies.

Journal Article↗
PubMed1990

Understanding structural relationships in proteins of unsolved three-dimensional structure.

The locations of functionally important sequences and general structural motifs have been assigned to Ile-tRNA synthetase. However, a function has not been established for some segments of the protein (e.g., CP1). The method of structural modeling described here cannot establish the details of a 3 A crystal structure, and, in contrast to a crystal structure, the precision of the model varies according to the extent of a sequence similarity or the functional importance of a region. In Ile-tRNA synthetase, the signature sequence and the flanking regions are likely to be similar in structure to the proteins on which the model is based. For other regions, it may be possible to build a three-dimensional model by connecting well defined regions and refining the positions of the connecting elements by energy minimization. Structural modelling of this kind must be done cautiously, because the order and orientation of the elements of a structural motif can change in subtle ways. In the case of Tyr-tRNA synthetase, the beta-strand nearest the N-terminus is the outermost strand of the nucleotide binding fold; in Met-tRNA synthetase, the same strand is innermost. Furthermore, the orientation of this strand may be antiparallel (Tyr-tRNA synthetase) or parallel (Met-tRNA synthetase). Because multiple structures that differ in their orientations of structural elements are possible, the structural analogies between proteins should not be naively extrapolated without independent experimental support. As described above, some regions of proteins tolerate internal deletions and insertions. This provides further experimental support for the practice of allowing for gaps in computer-generated sequence alignments. Nevertheless, because some regions are more tolerant of insertions and deletions than others, the structural and functional significance of a region of broken alignment must be assessed carefully. All gaps in sequence alignments cannot be treated equally, and each must be evaluated within its own context. In the synthetases of known structure, structural analogy can be used to identify important functional elements. For example, the amino acid binding site of Met-tRNA synthetase might be formed, at least in part, by a peptide that encompasses Ala50; this amino acid aligns with Gly94 of the Ile-tRNA synthetase. This is an example in which results on a protein of unknown structure (Ile-tRNA synthetases) can lead to identification of a potential substrate binding site in a protein of known structure (Met-tRNA synthetase).

Amino Acid Sequence↗
PubMed1995

Three-dimensional solution structure of the oxidized high potential iron-sulfur protein from Chromatium vinosum through NMR. Comparative analysis with the solution structure of the reduced species.

The NMR solution structure of the oxidized HiPIP from Chromatium vinosum has been solved. Despite the fact that the protein is paramagnetic, 85% of the 1H and 80% of the 15N signals have been assigned. Through 1537 NOEs, out of which 1142 were found to be relevant for the structure determination, a family of structures has been obtained by distance geometry calculations. These structures have then been subjected to restrained energy minimization (REM) and restrained molecular dynamics (RMD) calculations in vacuum. Finally, the mean structure of the RMD family has been treated through RMD in water. The RMSD values for the backbone and heavy atoms within the RMD family are 0.57 +/- 0.14 and 1.08 +/- 0.16 A, respectively. These values together with other parameters indicate that the structure is of good quality and as good as the structure of the reduced protein. The RMDw structures of the reduced and oxidized proteins are different beyond the experimental indetermination. The set of constraints for the reduced and oxidized forms have been used to treat the available X-ray structure by RMD in water. The two structures generated in this way are quite similar to their respective solution structures, thus confirming that the experimental constraints are capable of yielding two different structures from the same starting structural model. This is the first time that independently determined solution structures of two redox states of a paramagnetic protein are available. Differences between them and the X-ray structure are discussed.

Amino Acid Sequence↗
PubMed1999

Local interactions drive the formation of nonnative structure in the denatured state of human alpha-lactalbumin: a high resolution structural characterization of a peptide model in aqueous solution.

There are a small number of peptides derived from proteins that have a propensity to adopt structure in aqueous solution which is similar to the structure they possess in the parent protein. There are far fewer examples of protein fragments which adopt stable nonnative structures in isolation. Understanding how nonnative interactions are involved in protein folding is crucial to our understanding of the topic. Here we show that a small, 11 amino acid peptide corresponding to residues 101-111 of the protein alpha-lactalbumin is remarkably structured in isolation in aqueous solution. The peptide has been characterized by 1H NMR, and 170 ROE-derived constraints were used to calculate a structure. The calculations yielded a single, high-resolution structure for residues 101-107 that is nonnative in both the backbone and side-chain conformations. In the pH 6.5 crystal structure, residues 101-105 are in an irregular turn-like conformation and residues 106-111 form an alpha-helix. In the pH 4.2 crystal structure, residues 101-105 form an alpha-helix, and residues 106-111 form a loopike structure. Both of these structures are significantly different from the conformation adopted by our peptide. The structure in the peptide model is primarily the result of local side-chain interactions that force the backbone to adopt a nonnative 310/turn-like structure in residues 103-106. The structure in aqueous solution was compared to the structure in 30% trifluoroethanol (TFE), and clear differences were observed. In particular, one of the side-chain interactions, a hydrophobic cluster involving residues 101-105, is different in the two solvents and residues 107-111 are considerably more ordered in 30% TFE. The implications of the nonnative structure for the folding of alpha-lactalbumin is discussed.

Circular Dichroism↗
PubMed1987

Kepiński's functional structures, Kohonen's topological structures, aphasia and apraxia.

The concept of functional structures was introduced by Kepiński. At the Second Scandinavian Congress on Image Analysis in 1981 Kohonen provided evidence that the map of signals has the same topological order as the map of reactions. These topological concepts can be applied also to logical structures. The same is true also of functional structures described by Kepiński in schizophrenia, which may be created or destroyed, but their topological order remains unaltered. Functional structures change in obscuration and in hallucinogen-induced psychodelic states. Fixed pathological structures characterized by an altered topological order occur in paranoia. In the case of amnestic aphasia single elements of the topological functional structures fall out-these elements represent terms which patient is unable to recall. In motor aphasia, on the other hand, damage concerns the topological functional structures of speech related movements. In sensory aphasia damage concerns topological functional structures in the sensory area. In Goldstein's amnestic apraxia there is a loss of some elements of the topological functional structures governing the movements. In ideational apraxia the damage concerns topological functional structures representing entire sets of motor function and especially their creation. In ideomotor apraxia the respective topological functional structures are retained, albeit inaccessible, due to a disturbance in the motor association. In motor apraxia the damage seems to concern the topological functional structures governing precise movements and located at a lower level, i.e., closer to the effector. Constructive apraxia seems to result from the disturbed creation of the respective functional structures. Similarly the hypermotility of a maniacal type has a smooth and purposeful character, as far as the relation to a particular situation is concerned, which suggests that the respective topological functional structures are preserved. On the other hand, in the hyperkinetic phase of catatonic schizophrenia, in which the patient performs sequences of incoherent aimless movements without any relation to the current situation and environment, these structures are supposedly altered.

Aphasia↗
PubMed1995

Discriminating compact nonnative structures from the native structure of globular proteins.

Prediction of the native tertiary structure of a globular protein from the primary sequence will require a potential energy model that can discriminate all nonnative structures from the native structure(s). A successful model must distinguish not only alternate structures that are very nonnative but also alternate structures that are compact and near-native. We describe here a method, based on molecular dynamics simulation, that allows generation of hundreds of compact alternate structures that are arbitrarily close to the native structure. In this way, a significant amount of conformational space in the neighborhood of the native structure can be sampled and these alternate structures can be used as a stringent test of protein folding models. We have used two sets of these alternate structures generated for six crystallographically characterized small globular proteins (1200 alternate structures in all) to test eight empirical energy models for their ability to discriminate alternate from native structures. Seven of the models fail to correctly identify at least some of the alternate structures as nonnative. An atomic solvation model is presented that succeeds in discriminating all 1200 alternate structures from native.

Amino Acid Sequence↗
PubMed1999

Structure of taq DNA polymerase shows a new orientation for the structure-specific nuclease domain.

Thermus aquaticus DNA polymerase I consists of the polymerase, the structure-specific nuclease and the vestigial editing nuclease domains. Three-dimensional structures of the native enzyme and its complex with DNA have already been reported. The structure of a complex with an inhibitory antibody has also been determined. The structure of the native enzyme in a different crystal form determined at 2.6 A is reported here. Optimized anomalous diffraction measurements made at the holmium L(III) edge were valuable in validating solutions obtained through molecular replacement. The structure of the polymerase domain is similar to those reported previously, while the relative orientation of the structure-specific nuclease domain is significantly different from those of the native enzyme and the DNA complex; it is, however, identical to that observed in the structure of the Fab complex. In the structures of the native enzyme and of the DNA complex reported previously, the active site of the structure-specific nuclease domain is too far from that of the polymerase domain, making it difficult to propose a structural model for the in vivo primer-excision and nick-translation activities of the enzyme. In the present structure, the two active sites are considerably closer. Taken together, the reported structure of the native enzyme, that of the Fab complex and the present structure imply that the different orientation of the structure-specific nuclease domain is probably a consequence of intrinsically high relative mobility between these two domains in this enzyme.

Catalytic Domain↗
PubMed2003

High-pressure structural trends of Group 15 elements: simple packed structures versus complex host-guest arrangements.

The Group 15 elements P, As, Sb, and Bi all have layered structures consisting of six-membered rings under ambient conditions and attain the body-centered cubic (bcc) structure at the highest pressures applied. In the intermediate pressure region, however, phosphorus and its heavier congeners behave profoundly differently. In this region P first attains the open packed simple cubic (sc) structure for a wide range of pressures and then transforms into the rarely observed simple hexagonal (sh) structure. For the heavier congeners complex, incommensurately modulated host-guest structures emerge as intermediate pressure structures. We investigated the high-pressure behavior of P and As by ab initio density functional calculations in which pseudopotentials and a plane wave basis set were employed. The incommensurately modulated high-pressure structure of As was approximated by a supercell. Our calculations reproduced the experimentally established pressure stability ranges of the sc and sh structures for P and the host-guest structure for As very well. We found that the sc and especially the sh structure are decisively stabilized by the admixture of d states in the occupied levels of the electronic structure. This admixture releases s-s antibonding states above the Fermi level (s-d mixing). With pressure, s-d mixing increases rapidly for P, whereas it remains at a low level for As. As a consequence, the band energy contribution to the total energy determines the structural stability for P in the intermediate pressure region, giving rise to simple packed structures. On the other hand, in the intermediate pressure region of the heavier Group 15 elements, a delicate interplay between the electrostatic Madelung energy and the band energy leads to the formation of complex structures.

Journal Article↗
PubMed2002

The solution structure of reduced dimeric copper zinc superoxide dismutase. The structural effects of dimerization.

The solution structure of homodimeric Cu2Zn2 superoxide dismutase (SOD) of 306 aminoacids was determined on a 13C, 15N and 70% 2H labeled sample. Two-thousand eight-hundred and five meaningful NOEs were used, of which 96 intersubunit, and 115 dihedral angles provided a family of 30 conformers with an rmsd from the average of 0.78 +/- 0.11 and 1.15 +/- 0.09 A for the backbone and heavy atoms, respectively. When the rmsd is calculated for each subunit, the values drop to 0.65 +/- 0.09 and 1.08 +/- 0.11 A for the backbone and heavy atoms, respectively. The two subunits are identical on the NMR time scale, at variance with the X-ray structures that show structural differences between the two subunits as well as between different molecules in the unit cell. The elements of secondary structure, i.e. eight beta sheets, are the same as in the X-ray structures and are well defined. The odd loops (I, III and V) are well resolved as well as loop II located at the subunit interface. On the contrary, loops IV and VI show some disorder. The residues of the active cavity are well defined whereas within the various subunits of the X-ray structure some are disordered or display different orientation in different X-ray structure determinations. The copper(I) ion and its ligands are well defined. This structure thus represents a well defined model in solution relevant for structure-function analysis of the protein. The comparison between the solution structure of monomeric mutants and the present structure shows that the subunit-subunit interactions increase the order in loop II. This has the consequences of inducing the structural and dynamic properties that are optimal for the enzymatic function of the wild-type enzyme. The regions 37-43 and 89-95, constituting loops III and V and the initial part of the beta barrel and showing several mutations in familial amyotrophis lateral sclerosis (FALS)-related proteins have a quite extensive network of H-bonds that may account for their low mobility. Finally, the conformation of the key Arg143 residue is compared to that in the other dimeric and monomeric structures as well as in the recently reported structure of the CCS-superoxide dismutase (SOD) complex.

Deuterium↗
PubMed2003

Interrelationships between structural parameters of cancellous bone reveal accelerated structural change at low bone volume.

UNLABELLED: This study shows that change to cancellous bone structure is bone volume-dependent in a nonlinear manner. At low bone volume (< 15%), trabecular thickness and trabecular separation change at a much greater rate than at higher bone volume. This suggests that the structural integrity of the cancellous bone may become rapidly compromised when bone volume falls below a critical value. INTRODUCTION: While bone mass is the major determinant of bone strength, this mass-based paradigm does not fully account for the contribution of the bone microstructure to mechanical efficiency. Geometric models of cancellous bone structure have been formulated based on stylized representations of the trabecular elements, where the relationships between bone volume and bone surface of cancellous bone are complex and reflect the modulating effect on the cancellous bone structure of bone remodeling at the trabecular surfaces. Using the plate model of cancellous bone structure, the interrelationships between parameters of cancellous bone structure have been studied. MATERIALS AND METHODS: Two hundred eighty histological sections of human cancellous bone from eight skeletal sites were analyzed. The structural parameters of cancellous bone (BV/TV, BS/TV, BS/BV, Tb.Th, Tb.Sp, Tb.N, and TBPf) were obtained. RESULTS AND CONCLUSIONS: This study shows that change to cancellous bone structure is bone volume-dependent in a nonlinear manner. At low bone volume (< 15%), structural parameters of cancellous bone, such as trabecular thickness and trabecular separation, change at a much greater rate than at higher bone volume. This suggests that the structural integrity of the cancellous bone may become rapidly compromised when bone volume falls below a critical value. These data describe the complex relationships between bone mass and structure in cancellous bone that are often overlooked in the mass-based paradigm of bone strength. Histomorphometric descriptors of cancellous bone structure highlight the potential for accelerated deterioration of the structure with low bone volume, which leads to increased risk of fracture. From a clinical viewpoint, estimation of an individual's fracture risk is constrained to noninvasive techniques, which only provide bone mineral density or bone mineral content. Therefore, there is a need to better correlate measurement of bone mass with measurements of structural parameters.

Bone Density↗
PubMed2002

[Induction of petal-like structures from petals of Crocus sativus L. and the differentiation of style-stigma-like structures in vitro].

Firstly the petal of Crocus sativus L was cultured on the medium that supplemented with different combinations of hormones. The petal-like structures(PLS) were induced on medium, but the induction rates were different in various medium. The highest induction rate of petal-like structures was obtained on the media that was supplemented with NAA (4 mg/L) and KT (8 mg/L). The petal-like structures were subcultured on another media when the structure was produced on the explants and proliferate groups. The later media was used for inducing style-stigma-like structures(SSLS). The induction rate of style-stigma-like-structures in the petal-like structures group is much higher than the rate in the preceding work, and the maximum of style-stigma-like structures produced per explant was 30. The best result of style-stigma-like structures was observed on the petal-like structure groups which came from the third treatment. The differentiation rate of style-stigma-like structures is stable in the subcultures of petal-like structures. The result revealed that the induction frequency of style-stigma-like structures formed on the petal-like structures is higher than that form on the petals of C. sativus L.

Cell Differentiation↗
PubMed2000

The highly refined solution structure of the cytotoxic ribonuclease alpha-sarcin reveals the structural requirements for substrate recognition and ribonucleolytic activity.

alpha-Sarcin selectively cleaves a single phosphodiester bond in a universally conserved sequence of the major rRNA, that inactivates the ribosome. The elucidation of the three-dimensional solution structure of this 150 residue enzyme is a crucial step towards understanding alpha-sarcin's conformational stability, ribonucleolytic activity, and its exceptionally high level of specificity. Here, the solution structure has been determined on the basis of 2658 conformationally relevant distances restraints (including stereoespecific assignments) and 119 torsional angular restraints, by nuclear magnetic resonance spectroscopy methods. A total of 60 converged structures have been computed using the program DYANA. The 47 best DYANA structures, following restrained energy minimization by GROMOS, represent the solution structure of alpha-sarcin. The resulting average pairwise root-mean-square-deviation is 0.86 A for backbone atoms and 1.47 A for all heavy atoms. When the more variable regions are excluded from the analysis, the pairwise root-mean-square deviation drops to 0.50 A and 1.00 A, for backbone and heavy atoms, respectively. The alpha-sarcin structure is similar to that reported for restrictocin, although some differences are clearly evident, especially in the loop regions. The average rmsd between the structurally aligned backbones of the 47 final alpha-sarcin structures and the crystal structure of restrictocin is 1.46 A. On the basis of a docking model constructed with alpha-sarcin solution structure and the crystal structure of a 29-nt RNA containing the sarcin/ricin domain, the regions in the protein that could interact specifically with the substrate have been identified. The structural elements that account for the specificity of RNA recognition are located in two separate regions of the protein. One is composed by residues 51 to 55 and loop 5, and the other region, located more than 11 A away in the structure, is the positively charged segment formed by residues 110 to 114.

Allergens↗
PubMed1994

The 1.9 A structure of deoxy beta 4 hemoglobin. Analysis of the partitioning of quaternary-associated and ligand-induced changes in tertiary structure.

The crystal structure of the deoxygenated form of the human hemoglobin beta 4 tetramer (deoxy beta 4) has been determined and refined at a resolution of 1.9 A. A detailed comparison of the quaternary structures of carbonmonoxy-beta 4 (CO beta 4) and deoxy beta 4 shows that ligand binding to the beta 4 tetramer produces only slight movements of the subunits relative to each other. Therefore, unlike the hemoglobin alpha 2 beta 2 tetramer, where the transition from an unliganded T state tetramer to a liganded R state tetramer results in a large change in quaternary structure, beta 4 is locked in a quaternary structure that very closely resembles the R state. By comparing the high-resolution structures of T state deoxy alpha 2 beta 2, R state deoxy beta 4 and R state CO beta 4, it is possible to partition the changes in beta subunit tertiary structure into those that arise from changes in quaternary structure and those that result solely from ligand binding. Specifically, when viewed from the heme reference frame, comparison of the structures of T state deoxy alpha 2 beta 2 and R state deoxy beta 4 shows that the T-to-R quaternary structure transition induces changes in beta subunit tertiary structure that are approximately halfway toward the tertiary structure observed in liganded beta 4 and liganded alpha 2 beta 2. When viewed from the reference frame of the globin backbone atoms, the T-to-R quaternary structure transition induces a small rotation of the heme group and a shift of the "allosteric core" (the end of the F helix, the FG corner, the beginning of the G helix, and the heme group) away from the E helix. These movements open the ligand binding pocket and place the heme in a more symmetric position relative to the proximal histidine residue. Together, these effects work in unison to give the subunits of deoxy beta 4 a tertiary structure that has high ligand affinity.

Allosteric Site↗
PubMed1998

A Bayes-optimal sequence-structure theory that unifies protein sequence-structure recognition and alignment.

A rigorous Bayesian analysis is presented that unifies protein sequence-structure alignment and recognition. Given a sequence, explicit formulae are derived to select (1) its globally most probable core structure from a structure library; (2) its globally most probable alignment to a given core structure; (3) its most probable joint core structure and alignment chosen globally across the entire library; and (4) its most probable individual segments, secondary structure, and super-secondary structures across the entire library. The computations involved are NP-hard in the general case (3D-3D). Fast exact recursions for the restricted sequence singleton-only (1D-3D) case are given. Conclusions include: (a) the most probable joint core structure and alignment is not necessarily the most probable alignment of the most probable core structure, but rather maximizes the product of core and alignment probabilities; (b) use of a sequence-independent linear or affine gap penalty may result in the highest-probability threading not having the lowest score; (c) selecting the most probable core structure from the library (core structure selection or fold recognition only) involves comparing probabilities summed over all possible alignments of the sequence to the core, and not comparing individual optimal (or near-optimal) sequence-structure alignments; and (d) assuming uninformative priors, core structure selection is equivalent to comparing the ratio of two global means.

Amino Acid Sequence↗