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PubMed1998

Protein three-dimensional structural databases: domains, structurally aligned homologues and superfamilies.

This paper reports the availability of a database of protein structural domains (DDBASE), an alignment database of homologous proteins (HOMSTRAD) and a database of structurally aligned superfamilies (CAMPASS) on the World Wide Web (WWW). DDBASE contains information on the organization of structural domains and their boundaries; it includes only one representative domain from each of the homologous families. This database has been derived by identifying the presence of structural domains in proteins on the basis of inter-secondary structural distances using the program DIAL [Sowdhamini & Blundell (1995), Protein Sci. 4, 506-520]. The alignment of proteins in superfamilies has been performed on the basis of the structural features and relationships of individual residues using the program COMPARER [Sali & Blundell (1990), J. Mol. Biol. 212, 403-428]. The alignment databases contain information on the conserved structural features in homologous proteins and those belonging to superfamilies. Available data include the sequence alignments in structure-annotated formats and the provision for viewing superposed structures of proteins using a graphical interface. Such information, which is freely accessible on the WWW, should be of value to crystallographers in the comparison of newly determined protein structures with previously identified protein domains or existing families.

Amino Acid Sequence↗
PubMed1993

The importance of short structural motifs in protein structure analysis.

Proteins tend to use recurrent structural motifs on all levels of organization. In this paper we first survey the topics of recurrent motifs on the local secondary structure level and on the global fold level. Then, we focus on the intermediate level which we call the short structural motifs. We were able to identify a set of structural building blocks that are very common in protein structure. We suggest that these building blocks can be used as an important link between the primary sequence and the tertiary structure. In this framework, we present our latest results on the structural variability of the extended strand motifs. We show that extended strands can be divided into three distinct structural classes, each with its own sequence specificity. Other approaches to the study of short structural motifs are reviewed.

Amino Acid Sequence↗
PubMed2000

Conserved structural features in class I major fimbrial subunits (Pilin) in gram-negative bacteria. Molecular basis of classification in seven subfamilies and identification of intrasubfamily sequence signature motifs which might Be implicated in quaternary structure.

Type 1 and P-pili are prototype members of Class I fimbriae produced by Gram-negative bacteria. Despite common structural characteristics, the low level of amino acid sequence conservation among the Class I major fimbrial subunits (pilins) indicates considerable evolutionary distance between members of this superfamily. We highlight here structural relatedness between Class I pilins from their two-dimensional sequence analysis using hydrophobic cluster analysis (HCA) and secondary structure predictions (PHD program). We present evidence that all members of the Class I pilin family have clear structural relatedness and suggest that classification based on phylogenetic analysis of Class I pilins into seven subfamilies correlates with differences in structural properties of the amino acid sequences. Using a sensitive alignment process (HCA), we identified 29 residues in topohydrophobic positions which probably play a prominent role in folding. The most striking aspects that distinguish the different pilin subfamilies are (i) large variation in the length of the loops connecting the structurally conserved regions and (ii) intrasubfamily sequence signature motifs located on regions predicted to be in the beta-conformation. We suggest that these "intrasubfamily sequence signature motifs" are part of interactive surfaces which participate in subunit-subunit interactions. These motifs prove highly useful in characterizing and classifying new Class I fimbriae that have not yet been described and whose sequence diverges appreciably from those of characterized groups. (After the submission of our manuscript, the experimental structure of Class I pilus subunits was published. In light of these actual pilin structures, a comparison has been made between the predicted results and the crystal structure in the Note Added in Proof.)

Amino Acid Motifs↗
PubMed1996

Solution structure of horse heart ferricytochrome c and detection of redox-related structural changes by high-resolution 1H NMR.

A model for the solution structure of horse heart ferricytochrome c has been determined by nuclear magnetic resonance spectroscopy combined with hybrid distance geometry-simulated annealing calculations. Forty-four highly refined structures were obtained using a total of 1671 distance constraints based on the observed magnitude of nuclear Overhauser effects and 58 torsion angle restrains based on the magnitude of determined J-coupling constants. The model incorporates six long-lived water molecules detected by pseudo-two-dimensional NOESY-TOCSY spectra. The all-residue root mean square deviation about the average structure is 0.33 +/- 0.04 A for the backbone N, C alpha, and C' atoms and 0.83 +/- 0.05 A for all heavy atoms. The overall topology of the model for solution structure is very similar to that seen in previously reported models for crystal structures of homologous c-type cytochromes though there are a number of significant differences in detailed aspects of the structure. Two of the three main helices display localized irregularities in helical hydrogen bonding resulting in bifurcation of main chain hydrogen bond acceptor carbonyls. The N- and C-terminal helices are tightly packed and display several interhelical interactions not seen in reported crystal models. To provide an independent measure of the accuracy of the model for the oxidized protein, the expected pseudocontact shifts induced by the spin 1/2 iron were compared to the observed redox-dependent chemical shift changes. These comparisons confirm the general accuracy of the model for the oxidized protein and its observed differences with the structure of the reduced protein. The structures of the reduced and oxidized states of the protein provide a template to explain a range of physical and biological data spanning the redox properties, folding, molecular recognition, and stability of the cytochrome c molecule. For example, a redox-dependent reorganization of surface residues at the heme edge can be directly related to the redox behavior of the protein and thereby provides a previously undocumented linkage between structural change potentially associated with molecular recognition of redox partners and the fundamental parameters governing electron transfer.

Animals↗
PubMed2003

MASS: multiple structural alignment by secondary structures.

We present a novel method for multiple alignment of protein structures and detection of structural motifs. To date, only a few methods are available for addressing this task. Most of them are based on a series of pairwise comparisons. In contrast, MASS (Multiple Alignment by Secondary Structures) considers all the given structures at the same time. Exploiting the secondary structure representation aids in filtering out noisy results and in making the method highly efficient and robust. MASS disregards the sequence order of the secondary structure elements. Thus, it can find non-sequential and even non-topological structural motifs. An important novel feature of MASS is subset alignment detection: It does not require that all the input molecules be aligned. Rather, MASS is capable of detecting structural motifs shared only by a subset of the molecules. Given its high efficiency and capability of detecting subset alignments, MASS is suitable for a broad range of challenging applications: It can handle large-scale protein ensembles (on the order of tens) that may be heterogeneous, noisy, topologically unrelated and contain structures of low resolution.

Algorithms↗
PubMed2001

A proposed structural model for amyloid fibril elongation: domain swapping forms an interdigitating beta-structure polymer.

We propose a model illustrating how proteins, which differ in their overall sequences and structures, can form the propagating, twisted beta-sheet conformations, characteristic of amyloids. Some cases of amyloid formation can be explained through a "domain swapping" event, where the swapped segment is either a beta-hairpin or an unstable conformation which can partially unfold and assume a beta-hairpin structure. As in domain swapping, here the swapped beta-hairpin is at the edge of the structure, has few (if any) salt bridges and hydrogen bonds connecting it to the remainder of the structure and variable extents of buried non-polar surface areas. Additionally, in both cases the swapped piece constitutes a transient "building block" of the structure, with a high population time. Whereas in domain swapping the swapped fragment has been shown to be an alpha-helix, loop, strand or an entire domain, but so far not a beta-hairpin, despite the large number of cases in which it was already detected, here swapping may involve such a structural motif. We show how the swapping of beta-hairpins would form an interdigitated, twisted beta-sheet conformation, explaining the remarkable high stability of the protofibril in vitro. Such a swapping mechanism is attractive as it involves a universal mechanism in proteins, critical for their function, namely hinge-bending motions. Our proposal is consistent with structural superpositioning of mutational variants. While the overall r.m.s.d.s of the wild-type and mutants are small, the proposed hinge-bending region consistently shows larger deviations. These larger deviations illustrate that this region is more prone to respond to the mutational changes, regardless of their location in the sequence or in the structure. Nevertheless, above all, we stress that this proposition is hypothetical, since it is based on assumptions lacking definitive experimental support.

Amyloid↗
PubMed1999

Exploring the dynamic information content of a protein NMR structure: comparison of a molecular dynamics simulation with the NMR and X-ray structures of Escherichia coli ribonuclease HI.

The multiconformer nature of solution nuclear magnetic resonance (NMR) structures of proteins results from the effects of intramolecular dynamics, spin diffusion and an uneven distribution of structural restraints throughout the molecule. A delineation of the former from the latter two contributions is attempted in this work for an ensemble of 15 NMR structures of the protein Escherichia coli ribonuclease HI (RNase HI). Exploration of the dynamic information content of the NMR ensemble is carried out through correlation with data from two crystal structures and a 1.7-ns molecular dynamics (MD) trajectory of RNase HI in explicit solvent. Assessment of the consistency of the crystal and mean MD structures with nuclear Overhauser effect (NOE) data showed that the NMR ensemble is overall more compatible with the high-resolution (1.48 A) crystal structure than with either the lower-resolution (2.05 A) crystal structure or the MD simulation. Furthermore, the NMR ensemble is found to span more conformational space than the MD simulation for both the backbone and the sidechains of RNase HI. Nonetheless, the backbone conformational variability of both the NMR ensemble and the simulation is especially consistent with NMR relaxation measurements of two loop regions that are putative sites of substrate recognition. Plausible side-chain dynamic information is extracted from the NMR ensemble on the basis of (i) rotamericity and syn-pentane character of variable torsion angles, (ii) comparison of the magnitude of atomic mean-square fluctuations (msf) with those deduced from crystallographic thermal factors, and (iii) comparison of torsion angle conformational behavior in the NMR ensemble and the simulation. Several heterogeneous torsion angles, while adopting non-rotameric/syn-pentane conformations in the NMR ensemble, exist in a unique conformation in the simulation and display low X-ray thermal factors. These torsions are identified as sites whose variability is likely to be an artifact of the NMR structure determination procedure. A number of other torsions show a close correspondence between the conformations sampled in the NMR and MD ensembles, as well as significant correlations among crystallographic thermal factors and atomic msf calculated from the NMR ensemble and the simulation. These results indicate that a significant amount of dynamic information is contained in the NMR ensemble. The relevance of the present findings for the biological function of RNase HI, protein recognition studies, and previous investigations of the motional content of protein NMR structures are discussed.

Cluster Analysis↗
PubMed2003

Structural studies on MtRecA-nucleotide complexes: insights into DNA and nucleotide binding and the structural signature of NTP recognition.

RecA protein plays a crucial role in homologous recombination and repair of DNA. Central to all activities of RecA is its binding to Mg(+2)-ATP. The active form of the protein is a helical nucleoprotein filament containing the nucleotide cofactor and single-stranded DNA. The stability and structure of the helical nucleoprotein filament formed by RecA are modulated by nucleotide cofactors. Here we report crystal structures of a MtRecA-ADP complex, complexes with ATPgammaS in the presence and absence of magnesium as well as a complex with dATP and Mg+2. Comparison with the recently solved crystal structures of the apo form as well as a complex with ADP-AlF4 confirms an expansion of the P-loop region in MtRecA, compared to its homologue in Escherichia coli, correlating with the reduced affinity of MtRecA for ATP. The ligand bound structures reveal subtle variations in nucleotide conformations among different nucleotides that serve in maintaining the network of interactions crucial for nucleotide binding. The nucleotide binding site itself, however, remains relatively unchanged. The analysis also reveals that ATPgammaS rather than ADP-AlF4 is structurally a better mimic of ATP. From among the complexed structures, a definition for the two DNA-binding loops L1 and L2 has clearly emerged for the first time and provides a basis to understand DNA binding by RecA. The structural information obtained from these complexes correlates well with the extensive biochemical data on mutants available in the literature, contributing to an understanding of the role of individual residues in the nucleotide binding pocket, at the molecular level. Modeling studies on the mutants again point to the relative rigidity of the nucleotide binding site. Comparison with other NTP binding proteins reveals many commonalties in modes of binding by diverse members in the structural family, contributing to our understanding of the structural signature of NTP recognition.

Adenosine Diphosphate↗
PubMed2001

Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes.

Emergence of drug-resistant mutants of HIV-1 protease is an ongoing problem in the fight against AIDS. The mechanisms governing resistance are both complex and varied. We have determined crystal structures of HIV-1 protease mutants, D30N, K45I, N88D, and L90M complexed with peptide inhibitor analogues of CA-p2 and p2-NC cleavage sites in the Gag-pol precursor in order to study the structural mechanisms underlying resistance. The structures were determined at 1.55-1.9-A resolution and compared with the wild-type structure. The conformational disorder seen for most of the hydrophobic side-chains around the inhibitor binding site indicates flexibility of binding. Eight water molecules are conserved in all 9 structures; their location suggests that they are important for catalysis as well as structural stability. Structural differences among the mutants were analyzed in relation to the observed changes in protease activity and stability. Mutant L90M shows steric contacts with the catalytic Asp25 that could destabilize the catalytic loop at the dimer interface, leading to its observed decreased dimer stability and activity. Mutant K45I reduces the mobility of the flap and the inhibitor and contributes to an enhancement in structural stability and activity. The side-chain variations at residue 30 relative to wild-type are the largest in D30N and the changes are consistent with the altered activity observed with peptide substrates. Polar interactions in D30N are maintained, in agreement with the observed urea sensitivity. The side-chains of D30N and N88D are linked through a water molecule suggesting correlated changes at the two sites, as seen with clinical inhibitors. Structural changes seen in N88D are small; however, water molecules that mediate interactions between Asn88 and Thr74/Thr31/Asp30 in other complexes are missing in N88D.

Amino Acid Substitution↗
PubMed1996

Solution structure of the superactive monomeric des-[Phe(B25)] human insulin mutant: elucidation of the structural basis for the monomerization of des-[Phe(B25)] insulin and the dimerization of native insulin.

The three-dimensional solution structure of des-[Phe(B25)] human insulin has been determined by nuclear magnetic resonance spectroscopy and restrained molecular dynamics calculations. Thirty-five structures were calculated by distance geometry from 581 nuclear Overhauser enhancement-derived distance constraints, ten phi torsional angle restraints, the restraints from 16 helical hydrogen bonds, and three disulfide bridges. The distance geometry structures were optimized using simulated annealing and restrained energy minimization. The average root-mean-square (r.m.s.) deviation for the best 20 refined structures is 1.07 angstroms for the backbone and 1.92 angstroms for all atoms if the less well-defined N and C-terminal residues are excluded. The helical regions are more well defined, with r.m.s. deviations of 0.64 angstroms for the backbone and 1.51 angstroms for all atoms. It is found that the des-[Phe(B25)] insulin is a monomer under the applied conditions (4.6 to 4.7 mM, pH 3.0, 310 K), that the overall secondary and tertiary structures of the monomers in the 2Zn crystal hexamer of native insulin are preserved, and that the conformation-averaged NMR solution structure is close to the structure of molecule 1 in the hexamer. The structure reveals that the lost ability of des-[Phe(B25)] insulin to self-associate is caused by a conformational change of the C-terminal region of the B-chain, which results in an intra-molecular hydrophobic interaction between Pro(B28) and the hydrophobic region Leu(B11)-Leu(B15) of the B-chain alpha-helix. This interaction interferes with the inter-molecular hydrophobic interactions responsible for the dimerization of native insulin, depriving the mutant of the ability to dimerize. Further, the structure displays a series of features that may explain the high potency of the mutant on the basis of the current model for the insulin-receptor interaction. These features are: a change in conformation of the C-terminal region of the B-chain, the absence of strong hydrogen bonds between this region and the rest of the molecule, and a relatively easy accessibility to the Val(A3) residue.

Amino Acid Sequence↗
PubMed1998

Structure determination of the three disulfide bond isomers of alpha-conotoxin GI: a model for the role of disulfide bonds in structural stability.

The three possible disulfide bonded isomers of alpha-conotoxin GI have been selectively synthesised and their structures determined by 1H NMR spectroscopy. alpha-Conotoxin GI derives from the venom of Conus geographus and is a useful neuropharmacological tool as it selectively binds to the nicotinic acetylcholine receptor (nAChR), a ligand-gated ion channel involved in nerve signal transmission. The peptide has the sequence ECCNPACGRHYSC-NH2, and the three disulfide bonded isomers are referred to as GI(2-7;3-13), GI(2-13;3-7) and GI(2-3;7-13). The NMR structure for the native isomer GI(2-7;3-13) is of excellent quality, with a backbone pairwise RMSD of 0.16 A for a family of 35 structures, and comprises primarily a distorted 310 helix between residues 5 to 11. The two non-native isomers exhibit multiple conformers in solution, with the major populated forms being different in structure both from each other and from the native form. Structure-activity relationships for the native GI(2-7;3-13) as well as the role of the disulfide bonds on folding and stability of the three isomers are examined. It is concluded that the disulfide bonds in alpha-conotoxin GI play a crucial part in determining both the structure and stability of the peptide. A trend for increased conformational heterogeneity was observed in the order of GI(2-7;3-13)<GI(2-13;3-7)<GI(2-3;7-13). It was found that the peptide bond joining Cys2 to Cys3 in GI(2-3;7-13) is predominantly trans, rather than cis as theoretically predicted. These structural data are used to interpret the varying nAChR binding of the non-native forms.A model for the binding of native GI(2-7;3-13) to the mammalian nAChR is proposed, with an alpha-subunit binding face made up of Cys2, Asn4, Pro5, Ala6 and Cys7 and a selectivity face, comprised of Arg9 and His10. These two faces orient the molecule between the alpha and delta subunits of the receptor. The structure of the CCNPAC sequence of the native GI(2-7;3-13) is compared to the structure of the identical sequence from the toxic domain of heat-stable enterotoxins, which forms part of the receptor binding region of the enterotoxins, but which has a different disulfide connectivity.

Amino Acid Sequence↗
PubMed1998

Prediction of local structure in proteins using a library of sequence-structure motifs.

We describe a new method for local protein structure prediction based on a library of short sequence pattern that correlate strongly with protein three-dimensional structural elements. The library was generated using an automated method for finding correlations between protein sequence and local structure, and contains most previously described local sequence-structure correlations as well as new relationships, including a diverging type-II beta-turn, a frayed helix, and a proline-terminated helix. The query sequence is scanned for segments 7 to 19 residues in length that strongly match one of the 82 patterns in the library. Matching segments are assigned the three-dimensional structure characteristic of the corresponding sequence pattern, and backbone torsion angles for the entire query sequence are then predicted by piecing together mutually compatible segment predictions. In predictions of local structure in a test set of 55 proteins, about 50% of all residues, and 76% of residues covered by high-confidence predictions, were found in eight-residue segments within 1.4 A of their true structures. The predictions are complementary to traditional secondary structure predictions because they are considerably more specific in turn regions, and may contribute to ab initio tertiary structure prediction and fold recognition.

Algorithms↗
PubMed2000

Generation of deviation parameters for amino acid singlets, doublets and triplets from three-dimentional structures of proteins and its implications for secondary structure prediction from amino acid sequences.

We present a new method, secondary structure prediction by deviation parameter (SSPDP) for predicting the secondary structure of proteins from amino acid sequence. Deviation parameters (DP) for amino acid singlets, doublets and triplets were computed with respect to secondary structural elements of proteins based on the dictionary of secondary structure prediction (DSSP)-generated secondary structure for 408 selected non-homologous proteins. To the amino acid triplets which are not found in the selected dataset, a DP value of zero is assigned with respect to the secondary structural elements of proteins. The total number of parameters generated is 15,432, in the possible parameters of 25,260. Deviation parameter is complete with respect to amino acid singlets, doublets, and partially complete with respect to amino acid triplets. These generated parameters were used to predict secondary structural elements from amino acid sequence. The secondary structure predicted by our method (SSPDP) was compared with that of single sequence (NNPREDICT) and multiple sequence (PHD) methods. The average value of the percentage of prediction accuracy for a helix by SSPDP, NNPREDICT and PHD methods was found to be 57%, 44% and 69% respectively for the proteins in the selected dataset. For b-strand the prediction accuracy is found to be 69%, 21% and 53% respectively by SSPDP, NNPREDICT and PHD methods. This clearly indicates that the secondary structure prediction by our method is as good as PHD method but much better than NNPREDICT method.

Amino Acid Sequence↗
PubMed2002

Three-dimensional solution structure of Tropidechis carinatus venom extract trocarin: a structural homologue of Xa and prothrombin activator.

Trocarin belongs to group D of prothrombin activators derived from snake venom of Tropidechis carinatus and is a rich non-hepatic source of Xa, the only known hepatic prothrombin activator. The structural and functional similarity with Xa makes trocarin an interesting target for exploring the structure-functional relationship with Xa. Herein we report a predicted complete three-dimensional all-atom structural model of trocarin equilibrated in explicit water using 4 ns of molecular dynamics simulation. The tertiary structure was modeled using the structure of human blood coagulation factor Xa. The conformational and structural features of trocarin are then compared with the X-ray crystal and solution simulation structures of human factor Xa. The modeled structure of trocarin has four individual domains (Gla, EGF1, EGF2 and SP) connected along the long axis with similar secondary structural elements to Xa. The simulations suggest that sodium ion binding in the serine protease domain is impaired in trocarin as compared to Xa. In contrast to Xa, for which the sodium ion forms an octahedral coordination network that brings two loop regions connecting four anti-parallel beta-sheets together, we do not find a similar pattern of network in trocarin. We observe that the difference in the binding pattern of sodium ion leads to a approximately 2-A "shrinkage" of the beta2 strand (B2), in comparison to human Xa, as marked by a shorter distance between 189Asp373 (S1-site residue) and 195Ser379 (active-site residue) in the B2 strand. We propose that these differences may be linked to the experimentally observed lower amidolytic activity of trocarin as compared to Xa.

Amino Acid Sequence↗
PubMed1991

Correlation of secondary structure with biological activity for a leader peptide: circular dichroism-derived structure and in vitro biological activities of preproparathyroid hormone peptide and its analogs.

Leader or signal sequences are specialized domains within precursor proteins which serve an essential role in interacting with the cellular secretory apparatus to enable intracellular transport and secretion of proteins. Despite many differences in primary amino acid sequences, signal domains interact with a common set of intracellular components, presumably because the signal sequences share an overall conformational similarity. In a few instances, mutant signal peptides from prokaryotes have been studied and their structures correlated with function (export) in vivo. A series of analogs of the precursor-specific region of preproparathyroid hormone have been prepared which contain substitutions of either proline or a charged amino acid within the hydrophobic core. These synthetic "mutants" have previously been evaluated in several in vitro assays to determine their functionality with regard to protein secretion and suitability as substrates for signal peptidase. The secondary structural content of each peptide, as well as the native sequence and sulfur-free analog, was determined in aqueous and nonaqueous conditions by circular dichroism (CD) as a function of time. The structures obtained were correlated with in vitro bioactivities. Unlike the findings or previous CD studies, all the peptides examined here had low to undetectable alpha-helical content in both aqueous and nonaqueous buffers. The unsubstituted and sulfur-free analogs had high (80-85%) beta-structure in aqueous conditions which was reduced to approximately 30% in nonaqueous solvent. The proline- and charged-substituted peptides contained about half the beta-structure content (35-55%) in aqueous buffer; in nonaqueous solvent their structure was similar to the unsubstituted peptides. The structure-activity correlates found were as follows: a high degree of structure (aqueous conditions) correlated with interaction with signal recognition particle and substrate suitability for signal peptidase; a low degree of structure (nonaqueous environment) correlated with activity in the translocation assay.

Amino Acid Sequence↗
PubMed2003

Structure of Mycobacterium tuberculosis single-stranded DNA-binding protein. Variability in quaternary structure and its implications.

Single-stranded DNA-binding protein (SSB) is an essential protein necessary for the functioning of the DNA replication, repair and recombination machineries. Here we report the structure of the DNA-binding domain of Mycobacterium tuberculosis SSB (MtuSSB) in four different crystals distributed in two forms. The structure of one of the forms was solved by a combination of isomorphous replacement and anomalous scattering. This structure was used to determine the structure of the other form by molecular replacement. The polypeptide chain in the structure exhibits the oligonucleotide binding fold. The globular core of the molecule in different subunits in the two forms and those in Escherichia coli SSB (EcoSSB) and human mitochondrial SSB (HMtSSB) have similar structure, although the three loops exhibit considerable structural variation. However, the tetrameric MtuSSB has an as yet unobserved quaternary association. This quaternary structure with a unique dimeric interface lends the oligomeric protein greater stability, which may be of significance to the functioning of the protein under conditions of stress. Also, as a result of the variation in the quaternary structure the path adopted by the DNA to wrap around MtuSSB is expected to be different from that of EcoSSB.

Amino Acid Sequence↗
PubMed2002

Structural proteomics: developments in structure-to-function predictions.

The major challenge for post-genomic research is to functionally assign and validate a large number of novel target genes and their corresponding proteins. Functional genomics approaches have, therefore, gained considerable attention in the quest to convert this massive data set into useful information. One of the crucial components for the functional understanding of unassigned proteins is the analysis of their experimental or modeled 3D structures. Structural proteomics initiatives are generating protein structures at an unprecedented rate but our current knowledge of 3D-structural space is still limited. Estimates on the completeness of the 3D-structural coverage of proteins vary but it is generally accepted that only a minority of the structural proteome has a template structure from which reliable conclusions can be drawn. Thus, structural proteomics has set out to build a map of protein structures that will represent all protein folds included in the 'global proteome'.

Amino Acid Sequence↗
PubMed1995

Structure and function of cytochromes P450: a comparative analysis of three crystal structures.

BACKGROUND: Cytochromes P450 catalyze the oxidation of a variety of hydrophobic substrates. Sequence identities between P450 families are generally low (10-30%), and consequently, the structure-function correlations among P450s are not clear. The crystal structures of P450terp and the hemoprotein domain of P450BM-3 were recently determined, and are compared here with the previously available structure of P450cam. RESULTS: The topology of all three enzymes is quite similar. The heme-binding core structure is well conserved, except for local differences in the I helices. The greatest variation is observed in the substrate-binding regions. The structural superposition of the proteins permits an improved sequence alignment of other P450s. The charge distribution in the three structures is similarly asymmetric and defines a molecular dipole. CONCLUSIONS: Based on this comparison we believe that all P450s will be found to possess the same tertiary structure. The ability to precisely predict other P450 substrate-contact residues is limited by the extreme structural heterogeneity in the substrate-recognition regions. The central I-helix structures of P450terp and P450BM-3 suggest a role for helix-associated solvent molecules as a source of catalytic protons, distinct from the mechanism for P450cam. We suggest that the P450 molecular dipole might aid in both redox-partner docking and proton recruitment for catalysis.

Amino Acid Sequence↗