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PubMed2002

Primary structures of four trypsin inhibitor E homologs from venom of Dendroaspis angusticeps: structure-function comparisons with other dendrotoxin homologs.

Four trypsin inhibitor homologs, the first known from Dendroaspis angusticeps venom, were characterized using a combination of gel filtration, cation exchange, reverse-phase liquid chromatography, Edman degradation and mass spectrometry. The four toxins comprise two 57 residue and two 59 residue isoforms. The long toxins possess a Lys-Gln N-terminal extension lacked by the short toxins. The only other structural difference is an Arg/His replacement at position 55. The long Arg55 variant is identical to trypsin inhibitor E from the venom of Dendroaspis polylepis. The name epsilon-dendrotoxin is suggested so as to follow the nomenclature of Benishin, C.G., Sorensen, R.G., Brown, W.E., Krueger, B.K., Blaustein, M.P., 1988. Four polypeptide components of green mamba venom selectively block certain potassium channels in rat brain synaptosomes. Mol. Pharmacol. 34, 152-159. Among snake venom protease inhibitors, the epsilon-dendrotoxins are structurally most like the delta-dendrotoxins, with which they share only 64% of their residues. In addition, the epsilon-dendrotoxins display hydropathy profiles more like those of the alpha- and delta-dendrotoxins, than those of the trypsin inhibitors from snake venoms. Given the strong protease inhibitory activity of trypsin inhibitor E and the recently demonstrated weak K(+) channel inhibitory activity of two of these variants (Tytgat, J., Vandenberghe, I., Ulens, C., Van Beeumen, J., 2001. New polypeptide components purified from mamba venom. FEBS Lett. 491, 217-221), the epsilon-dendrotoxins represent structural and functional intermediates between the facilitatory toxins and the protease inhibitors.

Amino Acid Sequence↗
PubMed1998

Structures of spider toxins: hydroxyindole-3-acetylpolyamines and a new generalized structure of type-E compounds obtained from the venom of the Joro spider, Nephila clavata.

Facile structure determination of acylpolyamines, glutamatergic nerve blocker obtained from the venom of the Joro spider (Nephila clavata) was carried out with the use of micro-column LC/MS and high energy collision induced dissociation (CID) mass spectrometry. 6-hydroxyindole-3-acetyl was proposed previously as a putative partial structure, for the acyl moiety of hydroxyindole-type polyamines (NPTX-1 to -6). The NMR data obtained for NPTX-6, NPTX-687 and hydroxyindole-3-acetic acid which was released by acid hydrolysis of Nephila clavata crude venom extracts proved that the lipophilic head is the 4-hydroxyindole-3-acetic acid. Various hydroxyindole-3-acetyl polyamines were found in N. Clavata venom and characterized by mass spectrometry. As a result, type-E, a new class of generalized acylpolyamine structure was proposed in addition to the previously reported polyamine backbones type-A to -D.

Chromatography, Liquid↗
PubMed1999

Structural basis of Rab effector specificity: crystal structure of the small G protein Rab3A complexed with the effector domain of rabphilin-3A.

The small G protein Rab3A plays an important role in the regulation of neurotransmitter release. The crystal structure of activated Rab3A/GTP/Mg2+ bound to the effector domain of rabphilin-3A was solved to 2.6 A resolution. Rabphilin-3A contacts Rab3A in two distinct areas. The first interface involves the Rab3A switch I and switch II regions, which are sensitive to the nucleotide-binding state of Rab3A. The second interface consists of a deep pocket in Rab3A that interacts with a SGAWFF structural element of rabphilin-3A. Sequence and structure analysis, and biochemical data suggest that this pocket, or Rab complementarity-determining region (RabCDR), establishes a specific interaction between each Rab protein and its effectors. RabCDRs could be major determinants of effector specificity during vesicle trafficking and fusion.

Adaptor Proteins, Signal Transducing↗
PubMed1998

NPY Y1 antagonists: structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures.

Previously, omega-guanidino- and omega-aminoalkanamides, structurally derived from arpromidine-like histamine H2 receptor agonists, were reported as novel neuropeptide Y Y1 antagonists. Regardless of the backbone, they resemble BIBP 3226, an argininamide with high NPY Y1 receptor affinity and selectivity, with respect to nature and arrangement of the 'terminal' diaryl, guanidine, and hydroxyphenyl groups. Hybrid compounds were synthesized combining the argininamide backbone of BIBP 3226 or partial structures derived from the C-terminal dipeptide of NPY with characteristic substructures of arpromidine- or amide-type NPY antagonists. Additionally, some analogs of BIBP 3226 with reduced flexibility were prepared. Structure-activity relationships indicate that, in contrast to alkanamides, homologs and/or isomers of BIBP 3226 with vicinal arrangement of the phenyl rings have decreased Y1 antagonistic activity (Ca2+-assay in HEL cells). Replacement of the hydroxybenzyl group by an imidazole ring further decreases activity. It is concluded that the binding sites of NPY antagonists with one and with two basic groups are not identical. Analogs with a rigid tetrahydro-2-benzazepine or an indan group in place of the benzyl moiety in BIBP 3226 are active, indicating the role of the OH group and supporting the model proposed for the interaction of BIBP 3226 with the Y1 receptor.

Arginine↗
PubMed1979

The chemical structure and the crystalline structures of Bombyx mori silk fibroin.

Some recent data (i.e. published in the last ten years) on the chemical and crystalline structures of B. mori silk are reviewed. The main emphasis is put on the crystallizable portion of silk fibroin, including its chemical constitution and its molecular conformation (at the crystallographic unit-cell level) in the two crystalline modifications : the beta pleated sheet and the silk I structures. The structural aspects are based on a discussion of X-ray and electron diffraction data, and on conformational energy analyses of a model (Ala-Gly)n polypeptide of silk fibroin.

Amino Acid Sequence↗
PubMed1997

Structure-activity relationships of penem antibiotics: crystallographic structures and implications for their antimicrobial activities.

Twelve closely related crystal structures of the penem derivatives revealed a characteristic short contact of the oxygen atom in the C2 side-chains with the S1 atom. The side-chain conformations of the crystal structures showed a good correlation with the antimicrobial activity. In particular, the penems which show high antimicrobial activity have similar torsion angles for S1-C2-C1'-C2', suggesting that the disposition of the C2' atom would be important for binding to penicillin-interacting enzymes. Two conformations of the C6 hydroxyethyl group were observed in the crystal structures. Of those two, the conformation with a larger torsion angle (delta = 179.2 degrees) is deduced to be the enzyme-bound conformation in the Michaelis complex.

Anti-Bacterial Agents↗
PubMed1999

High-resolution structure of the conger eel galectin, congerin I, in lactose-liganded and ligand-free forms: emergence of a new structure class by accelerated evolution.

BACKGROUND: Congerin I is a member of the galectin (animal beta-galactoside-binding lectin) family and is found in the skin mucus of conger eel. The galectin family proteins perform a variety of biological activities. Because of its histological localization and activity against marine bacteria and starfish embryos, congerin I is thought to take part in the eels' biological defense system against parasites. RESULTS: The crystal structure of congerin I has been determined in both lactose-liganded and ligand-free forms to 1. 5 A and 1.6 A resolution, respectively. The protein is a homodimer of 15 kDa subunits. Congerin I has a beta-sheet topology that is markedly different from those of known relatives. One of the beta-strands is exchanged between two identical subunits. This strand swap might increase the dimer stability. Of the known galectin complexes, congerin I forms the most extensive interaction with lactose molecules. Most of these interactions are substituted by similar interactions with water molecules, including a pi-electron hydrogen bond, in the ligand-free form. This observation indicates an increased affinity of congerin I for the ligand. CONCLUSIONS: The genes for congerin I and an isoform, congerin II, are known to have evolved under positive selection pressure. The strand swap and the modification in the carbohydrate-binding site might enhance the cross-linking activity, and should be the most apparent consequence of positive selection. The protein has been adapted to functioning in skin mucus that is in direct contact with surrounding environments by an enhancement in cross-linking activity. The structure of congerin I demonstrates the emergence of a new structure class by accelerated evolution under selection pressure.

Amino Acid Sequence↗
PubMed2003

The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity.

The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family and regulate signal transduction in response to environmental stress. Activation of JNK3, a neuronal-specific isoform, has been associated with neurological damage, and as such, JNK3 may represent an attractive target for the treatment of neurological disorders. The MAP kinases share between 50% and 80% sequence identity. In order to obtain efficacious and safe compounds, it is necessary to address the issues of potency and selectivity. We report here four crystal structures of JNK3 in complex with three different classes of inhibitors. These structures provide a clear picture of the interactions that each class of compound made with the kinase. Knowledge of the atomic interactions involved in these diverse binding modes provides a platform for structure-guided modification of these compounds, or the de novo design of novel inhibitors that could satisfy the need for potency and selectivity.

Adenosine Triphosphate↗
PubMed2001

Comparing protein structures: a Gaussian-based approach to the three-dimensional structural similarity of proteins.

This study describes a new method for comparing three-dimensional protein structures based on an optimal alignment of their steric fields. The method is based upon the use of spherical Gaussian functions located on individual atoms. This representation generates a flexible description of the underlying fold geometry of proteins that can be adjusted by changing the 'width' of the Gaussians. Reducing the width sharpens the representation and leads to a more 'atomlike' description; increasing the width creates a fuzzier representation that preserves the general shape features of the chain fold but with a consequent loss in atomic resolution. The width used in this study is based upon the features of individual atoms and provides a representation that is quite robust with respect to the variety of geometric features typically encountered in the alignment process. In addition, a post-alignment analysis is performed that generates sequence alignments from the corresponding structure alignments. An example, based on five mammalian and fungal matrix metalloproteinase crystal structures (human fibroblast collagenase, neutrophil collagenase, stromelysin, astacin, and adamalysin), illustrates a number of features of the Gaussian-based approach.

Amino Acid Sequence↗
PubMed2005

Protein structure similarity clustering and natural product structure as guiding principles in drug discovery.

The identification of new chemical entities that are capable of altering protein function lies at the heart of the hit and lead finding process, for which combinatorial chemistry has emerged as a powerful tool. Following the maturation of combinatorial chemistry and compound library development, it was soon recognized that biological relevance, design and diversity of a library are more important than library size. The universe of conceivable compounds is almost infinite, therefore, the decisive question arises: where is a biologically validated starting point in structural space from which to build a compound library to be found? As a new approach to address this complex problem, a synergistic strategy is presented, which is based on protein structure similarity clustering and natural product structure as guiding rationales.

Biological Factors↗
PubMed1993

Context dependence of protein secondary structure formation: the three-dimensional structure and stability of a hybrid between chymotrypsin inhibitor 2 and helix E from subtilisin Carlsberg.

The loop region of chymotrypsin inhibitor 2 from barley has been employed as a scaffold for testing the intrinsic propensity of a peptide fragment to form a secondary structure. The helix formation of the nine amino acid residue segment Lys-Gln-Ala-Val-Asp-Asn-Ala-Tyr-Ala of helix E from subtilisin Carlsberg has been studied by the construction of a hybrid consisting of chymotrypsin inhibitor 2 (CI2) where part of the active loop has been replaced by the nonapeptide. An expression system for a truncated form of CI2 where the 19 structureless residues of the N-terminus have been removed and Leu20 replaced by methionyl was constructed from the entire 83-residue wild-type CI2 gene by polymerase chain reaction methodology. The gene encoding the hybrid was constructed from the truncated inhibitor gene. The stability of the truncated inhibitor and of the hybrid toward guanidinium chloride denaturation was examined. From these measurements, the energy of unfolding in pure water was extrapolated to 30.5 +/- 1.0 kJ/mol for the truncated inhibitor and 10.9 +/- 0.3 kJ/mol for the hybrid. These energies show that the stability of CI2 is unaffected by the N-terminal truncation but severely decreased by the loop mutations. The three-dimensional structure of the hybrid protein has been determined in solution by nuclear magnetic resonance spectroscopy using 893 distance restraints and 84 torsional angle restraints. The average root-mean-square deviation (rmsd) of 15 structures compared to their geometrical average was 0.8 +/- 0.2 A for heavy backbone atoms and 1.3 +/- 0.2 A for all heavy atoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

Structure-function relationships of curaremimetic neurotoxin loop 2 and of a structurally similar segment of rabies virus glycoprotein in their interaction with the nicotinic acetylcholine receptor.

Peptides corresponding to portions of curaremimetic neurotoxin loop 2 and to a structurally similar segment of rabies virus glycoprotein were synthetically modified in order to gain information on structure-function relationships of neurotoxin loop 2 interactions with the acetylcholine receptor. Binding of synthetic peptides to the acetylcholine receptor of Torpedo electric organ membranes was assessed by measuring their ability to inhibit the binding of 125I-alpha-bungarotoxin to the receptor. The peptides showing the highest affinity for the receptor were a peptide corresponding to the sequence of loop 2 (residues 25-44) of Ophiophagus hannah (king cobra) toxin b (IC50 = 5.7 x 10(-6) M) and the structurally similar segment (residues 173-203) of CVS rabies virus glycoprotein (IC50 = 2.6 x 10(-6) M). These affinities were comparable to those of d-tubocurarine (IC50 = 3.4 x 10(-6) M) and suberyldicholine (IC50 = 2.5 x 10(-6) M). These results demonstrate the importance of loop 2 in the neurotoxin interaction with the receptor. N- and C-terminal deletions of the loop 2 peptides and substitution of residues invariant or highly conserved among neurotoxins were performed in order to determine the role of individual residues in binding. Residues 25-40 are the most crucial in the interaction with the acetylcholine receptor. Modifications involving Lys-27, Trp-29, Phe-33, Arg-37, and Gly-38 reduced affinity of binding. R37D and F33T modifications reduced the affinity of alpha-bungarotoxin residues 28-40 by an order of magnitude. Arg-37 may correspond to the positively charged quaternary ammonium group and Phe-33 to the hydrophobic acetyl methyl group of acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Crystal structure of unmodified tRNA(Gln) complexed with glutaminyl-tRNA synthetase and ATP suggests a possible role for pseudo-uridines in stabilization of RNA structure.

tRNA(2Gln) made in vitro by transcription with T7 RNA polymerase does not contain the pseudouridines at positions 38, 39, and 55, the 4-thiouridine at position 8, or any of the methylated bases found in the tRNA(2Gln) made in vivo. Cocrystals of unmodified tRNA(2Gln) complexed with glutaminyl-tRNA synthetase from Escherichia coli are isomorphous with those of the complex with modified tRNA(2Gln). A difference electron density map between the complexes with modified and unmodified tRNAs calculated at 2.5-A resolution shows no differences in the protein or tRNA structures, except for some very small shifts in atoms contacting the thiol at the 4 position of uridine 8 that are required to accommodate the smaller oxygen in the unmodified tRNA. Perhaps the most functionally significant change in the unmodified tRNA is the absence of the specifically bound water molecules that are observed to cross-link the N5 of the pseudo-uridines to their 5' phosphate. This suggests a possible role for pseudouridinylation in stabilization of the tRNA through water-mediated linking of these modified bases to the backbone, which is consistent with the lower thermal stability of the unmodified tRNA. An identical water-bridging structure is possible at four of the five other psuedo-uridines in known tRNA structures.

Adenosine Triphosphate↗
PubMed1993

Tertiary structures of class I ubiquitin-conjugating enzymes are highly conserved: crystal structure of yeast Ubc4.

The three-dimensional structure of a yeast ubiquitin-conjugating enzyme, encoded by the Saccharomyces cerevisiae UBC4 gene, has been determined at 2.7 A. The structure was solved using molecular replacement techniques and refined by simulated annealing to an R-factor of 0.198. Bond lengths and angles in the molecule have root mean square deviations from ideal values of 0.018 A and 4.0 degrees, respectively. Ubc4 is an alpha/beta protein with four alpha-helices and a four-stranded antiparallel beta-sheet. The ubiquitin-accepting cysteine is located in a cleft between two loops. Comparison with the recently determined structure of a different plant enzyme suggests that class I ubiquitin-conjugating enzymes are highly conserved in their three-dimensional folding. Except for two extra residues at the N- and the C-terminus of the plant enzyme, the C alpha atoms of the two enzymes can be superimposed with a root mean square deviation of only 1.52 A. Greater variations are found between the surfaces of the two molecules, as most of the identical residues between the two enzymes are either buried or clustered on the surface that lies adjacent to the ubiquitin-accepting cysteine. We suggest that this conserved surface functions in protein-protein binding during ubiquitin thiol ester formation.

Amino Acid Sequence↗
PubMed1985

Salt-dependent structural changes of neurohormones: lithium ions induce conformational rearrangements of ocytocin to a vasopressin-like structure.

The preferred average conformation and structural subdomain interactions of the nonapeptide hormones vasopressin and ocytocin have been analyzed through the determination of their hydrodynamic volume and the thermal coefficient of the frictional resistance to rotation of their tyrosine residue. A spherical gross shape and an ellipsoidal gross shape were assessed respectively for ocytocin and vasopressin by fluorescence polarization analysis. Investigation of the thermal coefficient of viscosity and the critical temperature of both hormones and analogues indicated that strong interactions hold together the two structural subdomains of ocytocin (the flexible six-membered ring and the COOH-terminal tripeptide tail). An opposite situation was found in the case of vasopressin where such interactions could not be detected between the rigid ring and the flexible COOH-terminal tail. Lithium ions were shown to promote ocytocin binding to specific neurophysin sites restricted, under standard conditions, to vasopressin. In the presence of lithium, the gross conformational shape of ocytocin becomes similar to that of vasopressin but in the absence of salt. In addition, the ocytocin ring becomes more rigid in the presence of lithium while decreasing interactions between the ring and the COOH-terminal tail were detected. It is proposed that lithium ions induce specific conformational rearrangements of ocytocin toward a vasopressin-like structure, allowing recognition of this hormonal ligand by a specific vasopressin binding domain of neurophysins.

Amino Acid Sequence↗
PubMed1989

Sequence- and structure-dependent DNA base dynamics: synthesis, structure, and dynamics of site and sequence specifically spin-labeled DNA.

A nitroxide spin-labeled analogue of thymidine (1a), in which the methyl group is replaced by an acetylene-tethered nitroxide, was evaluated as a probe for structural and dynamics studies of sequence specifically spin-labeled DNA. Residue 1a was incorporated into synthetic deoxyoligonucleotides by using automated phosphite triester methods. 1H NMR, CD, and thermal denaturation studies indicate that 1a (T*) does not significantly alter the structure of 5'-d(CGCGAATT*CGCG) from that of the native dodecamer. EPR studies on monomer, single-stranded, and duplexed DNA show that 1a readily distinguishes environments of different rigidity. Comparison of the general line-shape features of the observed EPR spectra of several small duplexes (12-mer, 24-mer) with simulated EPR spectra assuming isotropic motion suggests that probe 1a monitors global tumbling of small duplexes. Increasing the length of the DNA oligomers results in significant deviation from isotropic motion, with line-shape features similar to those of calculated spectra of objects with isotropic rotational correlation times of 20-100 ns. EPR spectra of a spin-labeled GT mismatch and a T bulge in long DNAs are distinct from those of spin-labeled Watson-Crick paired DNAs, further demonstrating the value of EPR as a tool in the evaluation of local dynamic and structural features in macromolecules.

Base Sequence↗
PubMed1981

Structural dimorphism of bile salt/lecithin mixed micelles. A possible regulatory mechanism for cholesterol solubility in bile? X-ray structure analysis.

The three-dimensional structure of bile salt/lecithin mixed micelles in 0.15 M saline was derived from X-ray small-angle scattering measurements under various conditions. Two essentially different types of micelles were detected. At bile salt:lecithin molar ratios lower than approximately 2:1, lamellar particles similar to a lecithin bilayer arrangement were found. The thickness of the bilayer is 5.1 nm for mixed micelles having a molar ratio of 1:1. The lateral dimensions of the micelle were found strongly dependent upon molar ratio, increasing as lecithin content increases. In addition, it appeared that under certain incompletely defined conditions vesicular particles having diameters in the region of more than 100 nm occur. A molecular model of this type of micelle has been derived by means of a thorough interpretation of the electron density distribution across the plane of the bilayer. This model is generally consistent with the "mixed-disk" model of Mazer et al. [Mazer, N. A., Kwasnick, R. F., Carey, M. C., & Benedek, G. B. (1977) Micellization, Solubilization, Microemulsions, Proc. Int. Symp. 1, 383-402] and thus differs from that proposed by Small [Small, D. M. (1967) Gastroenterology 52,607-610] and Dervichian [Dervichian, D. G. (1968) Adv. Chem. Ser. No. 84, 78-87]. At molar ratios exceeding 2:1, a different type of micelle structure was found. This is a highly isometrical particle of globular shape, probably having a centrosymmetric arrangement of the molecular constituents. At a 3:1 bile salt:lecithin molar ratio, the mean physiological ratio for human gallbladder bile, the diameter of this micelle is 6.2 nm. Provided that other bile constituents have no significant influence on the structure, it may reasonably be expected that native gallbladder bile contains micelles of this latter type. The prevalent balance between the two micellar forms may thus regulate the capacity of bile to transport cholesterol.

Bile Acids and Salts↗
PubMed2001

Structure of beta-ketoacyl-[acyl carrier protein] reductase from Escherichia coli: negative cooperativity and its structural basis.

The structure of beta-ketoacyl-[acyl carrier protein] reductase (FabG) from Escherichia coli was determined via the multiwavelength anomalous diffraction technique using a selenomethionine-labeled crystal containing 88 selenium sites in the asymmetric unit. The comparison of the E. coli FabG structure with the homologous Brassica napus FabG.NADP(+) binary complex reveals that cofactor binding causes a substantial conformational change in the protein. This conformational change puts all three active-site residues (Ser 138, Tyr 151, and Lys 155) into their active configurations and provides a structural mechanism for allosteric communication between the active sites in the homotetramer. FabG exhibits negative cooperative binding of NADPH, and this effect is enhanced by the presence of acyl carrier protein (ACP). NADPH binding also increases the affinity and decreases the maximum binding of ACP to FabG. Thus, unlike other members of the short-chain dehydrogenase/reductase superfamily, FabG undergoes a substantial conformational change upon cofactor binding that organizes the active-site triad and alters the affinity of the other substrate-binding sites in the tetrameric enzyme.

Alcohol Oxidoreductases↗