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PubMed2001

Structural basis for low catalytic activity in Lys49 phospholipases A2--a hypothesis: the crystal structure of piratoxin II complexed to fatty acid.

Asp49 plays a fundamental role in supporting catalysis by phospholipases A2 by coordinating the calcium ion which aids in the stabilization of the tetrahedral intermediate. In several myotoxins from the venoms of Viperidae snakes, this aspartic acid is substituted by lysine. The loss of calcium binding capacity by these mutants has become regarded as the standard explanation for their greatly reduced or nonexistent phospholipolytic activity. Here we describe the crystal structure of one such Lys49 PLA2, piratoxin-II, in which a fatty acid molecule is observed within the substrate channel. This suggests that such toxins may be active enzymes in which catalysis is interrupted at the stage of substrate release. Comparison of the present structure with other PLA2s, both active and inactive, identifies Lys122 as one of the likely causes of the increased affinity for fatty acid in Lys49 enzymes. Its interaction with the mainchain carbonyl of Cys29 is expected to lead to hyperpolarization of the peptide bond between residues 29 and 30 leading to an increased affinity for the fatty acid headgroup. This strongly bound fatty acid may serve as an anchor to secure the toxin within the membrane thus facilitating its pathological effects.

Amino Acid Sequence↗
PubMed2002

The crystal structure of KR-21042, an analgesic capsaicinoid.

The crystal structure of KR-21042, N-(3-Phenylpropyl)-4-hydroxy-3-methoxyphenylacetamide, was determined by single crystal X-ray diffraction analysis. The compound was recrystallized from a mixture of ethylacetate and n-hexane in monoclinic, space group P21/c, with a = 16.622(1), b = 6.215(1), c = 15.802(1) A, P= 104.97(1), and Z = 4. The calculated density is 1.261 g/cm3. The structure was solved by the direct method and refined by full matrix least-squares procedure to the final R value of 0.068 for 2332 observed reflections.

Analgesics↗
PubMed1999

Toward rational design of ribonuclease inhibitors: high-resolution crystal structure of a ribonuclease A complex with a potent 3',5'-pyrophosphate-linked dinucleotide inhibitor.

The crystal structure of ribonuclease A (RNase A) in complex with pdUppA-3'-p [5'-phospho-2'-deoxyuridine-3'-pyrophosphate (P'-->5') adenosine 3'-phosphate] has been determined at 1.7 A resolution. This dinucleotide is the most potent low molecular weight inhibitor of RNase A reported to date (K(i) = 27 nM) and is also effective against two major nonpancreatic RNases: eosinophil-derived neurotoxin and RNase-4; in all cases, tight binding in large part derives from the unusual 3',5'-pyrophosphate internucleotide linkage [Russo, N., and Shapiro, R. (1999) J. Biol. Chem. 274, 14902-14908]. The design of pdUppA-3'-p was based on the crystal structure of RNase A complexed with 5'-diphosphoadenosine 3'-phosphate (ppA-3'-p) [Leonidas, D. D., Shapiro, R., Irons, L. I., Russo, N., and Acharya, K. R. (1997) Biochemistry 36, 5578-5588]. The adenosine of pdUppA-3'-p adopts an atypical syn conformation not observed for standard adenosine nucleotides bound to RNase A. This conformation, which allows extensive interactions with Asn 67, Gln 69, Asn 71, and His 119, is associated with the placement of the 5'-beta-phosphate of the adenylate, rather than alpha-phosphate, at the site where substrate phosphodiester bond cleavage occurs. The contacts of the deoxyuridine 5'-phosphate portion of pdUppA-3'-p appear to be responsible for the 9-fold increased affinity of this compound as compared to ppA-3'-p: the uracil base binds to Thr 45 in the same manner as previous pyrimidine inhibitors, and the terminal 5'-phosphate is positioned to form medium-range Coulombic interactions with Lys 66. The full potential benefit of these added interactions is not realized because of compensatory losses of hydrogen bonds of Lys 7 and Gln 11 with the terminal 3'-phosphate and the adenylate 5'-alpha-phosphate, which were not predicted by modeling. The results reported here have important implications for the design of improved inhibitors of RNase A and for the development of therapeutic agents to control the activities of RNase homologues such as eosinophil-derived neurotoxin and angiogenin that have roles in human pathologies.

Adenosine Diphosphate↗
PubMed1999

The crystal structure of the RNA/DNA hybrid r(GAAGAGAAGC). d(GCTTCTCTTC) shows significant differences to that found in solution.

The crystal structure of the RNA/DNA hybrid r(GAAGAGAAGC). d(GCTTCTCTTC) has been solved and refined at 2.5 A resolution. The refinement procedure converged at R = 0.181 for all reflections in the range 20.0-2.5 A. In the crystal, the RNA/DNA hybrid duplex has an A' conformation with all but one of the nucleotide sugar moieties adopting a C3'- endo (N) conformation. Both strands in the double helix adopt a global conformation close to the A-form and the width of the minor groove is typical of that found in the crystal structures of other A-form duplexes. However, differences are observed between the RNA and DNA strands that make up the hybrid at the local level. In the central portion of the duplex, the RNA strand has backbone alpha, beta and gamma torsion angles that alternate between the normal gauche -/ trans / gauche + conformation and an unusual trans / trans / trans conformation. Coupled with this so-called 'alpha/gamma flipping' of the backbone torsion angles, the distance between adjacent phosphorous atoms on the RNA strand systematically varies. Neither of these phenomena are observed on the DNA strand. The structure of the RNA/DNA hybrid presented here differs significantly from that found in solution for this and other sequences. Possible reasons for these differences and their implications for the current model of RNase H activity are discussed.

Circular Dichroism↗
PubMed2006

Crystal structure of the SH3 domain of betaPIX in complex with a high affinity peptide from PAK2.

The p21-activated kinases (PAKs) are important effector proteins of the small GTPases Cdc42 and Rac and control cytoskeletal rearrangements and cell proliferation. The direct interaction of PAKs with guanine nucleotide exchange factors from the PIX/Cool family, which is responsible for the localization of PAK kinases to focal complexes in the cell, is mediated by a 24-residue peptide segment in PAKs and an N-terminal src homology 3 (SH3) domain in PIX/Cool. The SH3-binding segment of PAK contains the atypical consensus-binding motif PxxxPR, which is required for unusually high affinity binding. In order to understand the structural basis for the high affinity and specificity of the PIX-PAK interaction, we solved crystal structures for the N-terminal SH3 domain of betaPIX and for the complex of the atypical binding segment of PAK2 with the N-terminal SH3 domain of betaPIX at 0.92 A and 1.3A resolution, respectively. The asymmetric unit of the crystal contains two SH3 domains and two peptide ligands. The bound peptide adopts a conformation that allows for intimate contacts with three grooves on the surface of the SH3 domain that lie between the n-Src and RT-loops. Most notably, the arginine residue of the PxxxPR motif forms a salt-bridge and is tightly coordinated by a number of residues in the SH3 domain. This arginine-specific interaction appears to be the key determinant for the high affinity binding of PAK peptides. Furthermore, C-terminal residues of the peptide engage in additional interactions with the surface of the RT-loop, which significantly increases binding specificity. Compared to a recent NMR structure of a similar complex, our crystal structure reveals an alternate binding mode. Finally, we compare our crystal structure with the recently published betaPIX/Cbl-b complex structure, and suggest the existence of a molecular switch.

Amino Acid Sequence↗
PubMed2000

1.9 A resolution crystal structure of the Saccharomyces cerevisiae Ran-binding protein Mog1p.

The 1.9 A resolution X-ray crystal structure of Ran-binding protein Mog1p shows that it has a unique fold based on a six-stranded antiparallel beta-sheet backed on both sides by an extensive alpha-helix. The topology of some elements of Mog1p secondary structure resemble a portion of nuclear transport factor 2 (NTF2), but the hydrophobic cavity and surrounding negatively charged residues that are important in the NTF2-RanGDP interaction are not conserved in Mog1p. In addition to binding RanGTP, Mog1p forms a 1:1 complex with RanGDP and so binds Ran independent of its nucleotide state. Mog1p and NTF2 compete for binding to RanGDP indicating that their binding sites on RanGDP are sufficiently close to prevent both proteins binding simultaneously. Although there may be some overlap between the Mog1p and NTF2 binding sites on RanGDP, these sites are not identical. Sequence analysis of Mog1p homologues from Schizosaccharomyces pombe, human, and Caenorhabditis elegans in the context of the Mog1p crystal structure indicates the presence of a cluster of highly conserved surface residues consistent with an interaction site for Ran.

Alleles↗
PubMed2004

Crystal structure of transglutaminase 3 in complex with GMP: structural basis for nucleotide specificity.

Epidermal-type Transglutaminase 3 (TGase 3) is a Ca(2+)-dependent enzyme involved in the cross-linking of structural proteins required in the assembly of the cell envelope. We have recently shown that calcium-activated TGase 3, like TGase 2, can bind, hydrolyze, and is inhibited by GTP despite lacking structural homology with other GTP-binding proteins. Here we report the crystal structure determined at 2.0 A resolution of TGase 3 in complex with GMP to elucidate the structural features required for nucleotide recognition. Binding affinities for various nucleotides were found by fluorescence displacement to be as follows: guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) (0.4 microm), GTP (0.6 microm), GDP (1.0 microm), GMP (0.4 microm), and ATP (28.0 microm). Furthermore, we found that GMP binds as a reversible, noncompetitive inhibitor of TGase 3 transamidation activity, similar to GTPgammaS and GDP. A genetic algorithm similarity program (GASP) approach (virtual ligand screening) identified three compounds from the Lead Quest trade mark data base (Tripos Inc.) based on superimposition of GTPgammaS, GDP, and GMP guanine nucleotides from our crystal structures to generate the minimum align flexible fragment. These three were nucleotide analogs without a phosphate group containing the minimal binding motif for TGase 3 that includes a nucleoside recognition groove. Binding affinities were measured as follows: TP349915 (K(d) = 4.1 microm), TP395289 (K(d) = 38.5 microm), TP394305 (K(d) = 1.0 mm). Remarkably, these compounds do not inhibit but instead activate TGase 3 transamidation by about 10-fold. These results suggest that the nucleotide binding pocket in TGase 3 may be exploited to either enhance or inhibit the enzymatic activity as required for different therapeutic approaches.

Adenosine Triphosphate↗
PubMed2006

Preparation, crystal structure, and thermal stability of the cadmium sulfide nanoclusters Cd6S44+ and Cd2Na2S4+in the sodalite cavities of zeolite A (LTA).

The crystal structure and thermal stability of two cadmium sulfide nanoclusters prepared in zeolite A (LTA) have been studied by XPS, TGA, and single-crystal and powder XRD. The crystal structures of Cd2.4Na3.2(Cd6S4)0.4(Cd2Na2S)0.6(H2O)> or =5.8[Si12Al12O48]-LTA (a = 12.2919(7) A, crystal 1 (hydrated)) and /Cd4Na2(Cd2O)(Na2O)/[Si12Al12O48]-LTA (a = 12.2617(4) A, crystal 2 (dehydrated)) were determined by single-crystal methods in the cubic space group Pm3m at 294(1) K. Crystal 1 was prepared by ion exchange of Na12-LTA in an aqueous stream 0.05 M in Cd2+, followed by washing in a stream of water, followed by reaction in an aqueous stream 0.05 M in Na2S. Crystal 2 was made by dehydrating crystal 1 at 623 K and 1 x 10(-6) Torr for 3 days. In crystal 1, Cd6S4(4+) nanoclusters were found in and extending out of about 40% of the sodalite cavities. Central to each Cd6S4(4+) cluster is a Cd4S4 unit (interpenetrating Cd2+ and S2- tetrahedra with near Td symmetry, Cd-S = 2.997(24) A, Cd-S-Cd = 113.8(12) degrees, and S-Cd-S = 58.1(24) degrees). Each of the two remaining Cd2+ ions bonds radially through a 6-ring of the zeolite framework to a sulfide ion of this Cd4S4 unit (Cd-S = 2.90(8) A). In each of the remaining 60% of the sodalite cavities of crystal 1, a planar Cd2Na2S4+ cluster was found (Cd-S/Na-S = 2.35(5)/2.56(14) A and Cd-S-Cd/Na-S-Na = 122(5)/92(7) degrees). Cd6S4(4+) and Cd2Na2S4+ are stable within the zeolite up to about 700 K in air. Upon vacuum dehydration at 623 K, all sulfur was lost (crystal 2). Instead as anions, only two oxide ions remain per sodalite unit. One bridges between two Cd2+ ions (Cd2O2+, Cd-O = 2.28(3) A) and the other between two Na+ ions (Na2O, Na-O = 2.21(10) A).

Journal Article↗
PubMed1996

Synthesis of a Heteroditopic Cryptand Capable of Imposing a Distorted Coordination Geometry onto Cu(II): Crystal Structures of the Cryptand (L), [Cu(L)(CN)](picrate), and [Cu(L)(NCS)](picrate) and Spectroscopic Studies of the Cu(II) Complexes.

The synthesis of a new macrobicyclic cryptand (L) with heteroditopic receptor sites has been achieved in good yields by the [1 + 1] Schiff base condensation of tris(2-aminoethyl)amine (tren) with the tripodal trialdehyde, tris{[2-(3-(oxomethyl)phenyl)oxy]ethyl}amine at 5 degrees C temperature. The crystal structure of L (P2(1)/c, a = 10.756 (5) Å, b = 27.407(9) Å, c = 12.000(2) Å, beta = 116.22(3) degrees, Z = 4, R = 0.060, R(w) = 0.058) shows a pseudo-3-fold symmetry axis passing through the two bridgehead nitrogens. This symmetry is maintained in chloroform solution also, as indicated from its (1)H-NMR spectral data. The cryptand readily forms inclusion complexes with the Cu(II) ion at the tren end of the cavity. The tetracoordinated Cu(II) cryptate (1) thus formed with Cu(picrate)(2) exhibits a very small A(II) value (60 x 10(-)(4) cm(-)(1)) in its EPR spectrum and low-energy ligand field bands in its electronic spectrum in MeCN at room temperature. The bound Cu(II) ion readily accepts the anions CN(-), SCN(-), or N(3)(-), forming distorted trigonal bipyramidal complexes (2-4). The crystal structure of [Cu(L)(CN)](picrate) (2) (P2(1)/C, a = 13.099(1) Å, b = 11.847(8) Å, c = 25.844(7) Å, beta = 91.22(1) degrees, Z = 4, R = 0.056, R(w) = 0.054) has been determined. The equatorial coordination is provided by the three secondary amino N atoms of the tren unit in L, while the two axial positions are occupied by the bridgehead N of the tren unit and the C atom of the cyanide group. One of the equatorial Cu-N bond distances is 2.339(6) Å, which is longer than normal values. The crystal structure of [Cu(L)(NCS)](picrate) (3) (C2/c, a = 47.889(10) Å, b = 10.467(5) Å, c = 16.922(2) Å, beta = 93.90(2) degrees, Z = 8, R = 0.054, R(w) = 0.055) shows the coordination geometry around the Cu(II) ion to be very similar to that in the case of 2. The electronic spectral and EPR spectral data obtained on 2-4 are characteristic of trigonal bipyramidal Cu(II) complexes. The three meta-substituted benzene rings present in L makes the donor atom somewhat rigid in nature which enforces a distorted geometry around the Cu(II) ion.

Journal Article↗
PubMed1992

Conformational investigation of alpha, beta-dehydropeptides. Part III. Molecular and crystal structure of acetyl-L-prolyl-alpha, beta-dehydrovaline methylamide.

The crystal structure of Ac-Pro-delta Val-NHCH3 was examined to determine the influence of the alpha,beta-dehydrovaline residue on the nature of peptide conformation. The peptide crystallizes from methanol-diethyl ether solution at 4 degrees in needle-shaped form in orthorhombic space group P2(1)2(1)2(1) with a = 11.384(2) A, b = 13.277(2) A, c = 9.942(1) A, V = 1502.7(4) A3, Z = 4, Dm = 1.17 g.cm-3 and Dc = 1.18 g.cm-3. The structure was solved by direct methods using SHELXS-86 and refined to an R value of 0.057 for 1922 observed reflections. The peptide is found to adopt a beta-bend between the type I and the type III conformation with phi 1 = -68.3(4) degrees, psi 1 = -20.1(4) degrees, phi 2 = -73.5(4) degrees and psi 2 = -14.1(4) degrees. An intramolecular hydrogen bond between the carbonyl oxygen of ith residue and the NH of (i + 3)th residue stabilizes the beta-bend. An additional intermolecular N...O hydrogen bond joins molecules into infinite chains. In the literature described crystal structures of peptides having a single alpha,beta-dehydroamino acid residue in the (i + 2) position and forming a beta-bend reveal a type II conformation.

Amino Acid Sequence↗
PubMed1998

Crystal structure of the abl-SH3 domain complexed with a designed high-affinity peptide ligand: implications for SH3-ligand interactions.

The Abl-SH3 domain is implicated in negative regulation of the Abl kinase by mediating protein-protein interactions. High-affinity SH3 ligands could compete for these interactions and specifically activate the Abl kinase, providing control and a better understanding of the molecular interactions that underlie diseases where SH3 domains are involved. The p41 peptide (APSYSPPPPP) is a member of a group of peptide ligands designed to bind specifically the Abl-SH3 domain. It binds to Abl-SH3 with a Kd of 1.5 microM, whereas its affinity for the Fyn-SH3 domain is 273 microM. We have determined the crystal structure of the Abl-SH3 domain in complex with the high-affinity peptide ligand p41 at 1.6 A resolution. In the crystal structure, this peptide adopts a polyproline type II helix conformation through residue 5 to 10, and it binds in type I orientation to the Abl-SH3 domain. The tyrosine side-chain in position 4 of the peptide is hydrogen bonded to two residues in the RT-loop of the Abl-SH3 domain. The tight fit of this side-chain into the RT-loop pocket is enhanced by conformational adjustment of the main chain at position 5. The SH3 ligand peptides can be divided into two distinct parts. The N-terminal part binds to the SH3 domain in the region formed by the valley between the nSrc and RT-loops. It determines the specificity for different SH3 domains. The C-terminal part adopts a polyproline type II helix conformation. This binds to a well-conserved hydrophobic surface of the SH3 domain. Analysis of two "half"-peptides, corresponding to these ligand parts, shows that both are essential components for strong binding to the SH3 domains. The crystal structure of the Abl-SH3:p41 complex explains the high affinity and specificity of the p41 peptide towards the Abl-SH3 domain, and reveals principles that will be exploited for future design of small, high-affinity ligands to interfere efficiently with the in vivo regulation of Abl kinase activity.

Amino Acid Sequence↗
PubMed1997

Crystal Structure and Absorption Spectroscopy of a Neodymium(III) Complex with Triethylenetetraaminehexaacetic Acid, Na(3)[Nd(TTHA)].2.5NaClO(4).7.617H(2)O.

The crystal structure and absorption spectroscopy results of the Na(3)[Nd(TTHA)].2.5NaClO(4).7.617H(2)O compound are presented. The crystal structure of the complex was determined by X-ray analysis. Crystals are monoclinic, space group C2/c, with a = 38.446(8) Å, b = 10.552(2) Å, c = 25.796(5) Å, beta = 130.51(3) degrees, and Z = 4. The structure consists of monomeric (triethylenetetraaminehexaacetato)neodymate anions, perchlorate anions, sodium cations, and water molecules. The Nd(III) ion adopts a 10-coordinate geometry with six oxygen atoms and four nitrogen atoms from a ligand molecule, which is best described as a bicapped square antiprism. Absorption spectra of a single crystal were measured at room and liquid helium temperatures. Intensities of the f-f transitions were analyzed on the basis of Judd-Ofelt theory. The good correspondence between the spectra of [Nd(TTHA)](3)(-) in solution and in the single crystal suggests close similarity of both coordination polyhedra.

Journal Article↗
PubMed2006

Interaction between the Z-type DNA duplex and 1,3-propanediamine: crystal structure of d(CACGTG)2 at 1.2 A resolution.

The crystal structure of a hexamer duplex d(CACGTG)(2) has been determined and refined to an R-factor of 18.3% using X-ray data up to 1.2 A resolution. The sequence crystallizes as a left-handed Z-form double helix with Watson-Crick base pairing. There is one hexamer duplex, a spermine molecule, 71 water molecules, and an unexpected diamine (Z-5, 1,3-propanediamine, C(3)H(10)N(2)) in the asymmetric unit. This is the high-resolution non-disordered structure of a Z-DNA hexamer containing two AT base pairs in the interior of a duplex with no modifications such as bromination or methylation on cytosine bases. This structure does not possess multivalent cations such as cobalt hexaammine that are known to stabilize Z-DNA. The overall duplex structure and its crystal interactions are similar to those of the pure-spermine form of the d(CGCGCG)(2) structure. The spine of hydration in the minor groove is intact except in the vicinity of the T5A8 base pair. The binding of the Z-5 molecule in the minor grove of the d(CACGTG)(2) duplex appears to have a profound effect in conferring stability to a Z-DNA conformation via electrostatic complementarity and hydrogen bonding interactions. The successive base stacking geometry in d(CACGTG)(2) is similar to the corresponding steps in d(CG)(3). These results suggest that specific polyamines such as Z-5 could serve as powerful inducers of Z-type conformation in unmodified DNA sequences with AT base pairs. This structure provides a molecular basis for stabilizing AT base pairs incorporated into an alternating d(CG) sequence.

Base Pairing↗
PubMed1994

Horse pancreatic lipase. The crystal structure refined at 2.3 A resolution.

Pancreatic lipase (EC 3.1.1.3) plays a key role in dietary fat digestion by converting triacylglycerols into 2-monoacylglycerols and free fatty acids in the intestine. Although the crystallographic structures of the human pancreatic lipase and of a human lipase-porcine colipase complex have been solved, no refined structure of pancreatic lipase has yet been published. The crystal structure of the horse enzyme was solved by the molecular replacement method from the model of the human pancreatic lipase and subsequently refined to 2.3 A resolution. The final model contains two molecules of 449 amino acid residues each in the asymmetric unit, 705 well-defined water molecules and two calcium ions. The two molecules in the asymmetric unit of the orthorhombic crystals are related by a 2-fold non-crystallographic symmetry axis as in the case of the human lipase. However, the association between the two molecules in their respective crystal forms is different. The overall molecular structure of the horse lipase is very similar to that of the human enzyme. The horse lipase is made up of two well-defined domains. The N-terminal domain which bears the active centre has a typical alpha/beta hydrolase fold topology. The C-terminal domain which is devoted to colipase binding has a beta-sheet sandwich topology. Comparison of equivalent C alpha atom positions between the final model of the horse lipase and the human lipase structure shows only slight differences which are mainly located in the C-terminal domain. The horse enzyme possesses the common features of the known mammalian and microbial lipases, in particular the "flap" covering the catalytic triad. In addition to more precise information concerning these features, the elucidation of the horse lipase crystal structure allowed us to better understand the structural basis of the kinetic behaviour of pancreatic lipases towards a soluble substrate, p-nitrophenyl acetate, and the different sensitivity of these enzymes towards limited proteolysis.

Amino Acid Sequence↗
PubMed2004

A simple molecule with a complex crystal structure: interplay of 31P solid-state NMR spectroscopy and single-crystal x-ray diffraction in the structure determination of a ruthenium diphosphine diamine complex.

A comprehensive 31P solid-state NMR study of Ru(eta1-Ph2PCH2CH2OCH3)2(eta2-en)Cl2 (en = ethylenediamine) (1), by 1D (contact time variation, inversion-recovery, SPARTAN) and 2D techniques (homonuclear J-resolved, SECSY) indicated that the crystal structure of 1 should be complex. The single-crystal x-ray structure determination confirmed the presence of eight independent molecules in the asymmetric unit, with 31P isotropic chemical shifts in the range 27.3-40.1 ppm, while the spans of the phosphorus chemical shift tensors are of the order of 170 ppm. Based on unique structural features and NMR data, one molecule has been tentatively assigned.

Algorithms↗
PubMed2001

The crystal structure of a novel mammalian lectin, Ym1, suggests a saccharide binding site.

Ym1, a secretory protein synthesized by activated murine peritoneal macrophages, is a novel mammalian lectin with a binding specificity to GlcN. Lectins are responsible for carbohydrate recognition and for mediating cell-cell and cell-extracellular matrix interactions in microbes, plants, and animals. Glycosaminoglycan heparin/heparan sulfate binding ability was also detected in Ym1. We report here the three-dimensional structure of Ym1 at 2.5-A resolution by x-ray crystallography. The crystal structure of Ym1 consists of two globular domains, a beta/alpha triose-phosphate isomerase barrel domain and a small alpha + beta folding domain. A notable electron density of sugar is detected in the Ym1 crystal structure. The saccharide is located inside the triose-phosphate isomerase domain at the COOH terminal end of the beta-strands. Both hydrophilic and hydrophobic interactions are noted in the sugar-binding site in Ym1. Despite the fact that Ym1 is not a chitinase, structurally, Ym1 shares significant homology with chitinase A of Serratia marcescens. Ym1 and chitinase A have a similar carbohydrate binding cleft. This study provides new structure information, which will lead to better understanding of the biological significance of Ym1 and its putative gene members.

Amino Acid Sequence↗
PubMed2002

Insights into integrin-ligand binding and activation from the first crystal structure.

Integrin receptors transduce bidirectional signals between extracellular adhesion molecules and intracellular cytoskeletal and signalling molecules. The structural basis of integrin signalling is unknown, but the recent publication of the first crystal structure of the extracellular domain of integrin alphaVbeta3 has provided a number of insights. In this review, previous structure-function analyses of integrins that have employed biochemical and molecular biological approaches are placed in the context of the crystal structure, and novel routes to the development of integrin antagonists are discussed.

Binding Sites↗
PubMed1991

Ionic interactions with parvalbumins. Crystal structure determination of pike 4.10 parvalbumin in four different ionic environments.

The crystal structure of the Ca-loaded form of pike 4.10 parvalbumin (minor component from pike muscle belonging to the beta phylogenetic series), with both its primary sites CD and EF occupied by Ca2+ ions and its third site occupied by an ammonium ion, as previously determined at 1.93 A resolution, has now been refined to a resolution of 1.65 A. The crystallization of this parvalbumin in different ionic environments has allowed three novel non-isomorphous crystalline forms to be obtained: (1) a first form, crystallized in the presence of a mixture of ammonium sulphate and manganese sulphate, for which all the cation binding sites in the protein are occupied by Mn2+; (2) a second form crystallized in the presence of MgSO4 as the precipitating agent, only differs from the Ca/NH4 form by the occupation of the third site by Mg2+, whereas the primary sites remain occupied by Ca2+; (3) a third form, also crystallized in the presence of MgSO4, corresponds to a well-defined molecular species with both the primary EF site and the third site occupied by Mg2+, whereas the primary CD site remains occupied by CA2+. The corresponding molecular structures reported here have been determined at resolutions between 1.8 and 2.4 A. The comparison of the different crystal structures allows the structural modifications accompanying the substitution of the primary sites by cations differing significantly in their ionic radii (Ca2+, Mn2+, Mg2+) to be investigated in detail, and it also leads to a precise description of the third site in a typical beta parvalbumin. The substitution Ca2+ by Mg2+ within the primary site EF is characterized by a "contraction" of the co-ordination sphere, with a decrease of the mean oxygen-metal distance by a value of 0.25 A and a decrease of the co-ordination number from 7 to 6, as a consequence of the loss of a bidentate ligand (Glu101), which becomes a monodentate one. Such an adaptation of the co-ordination sphere around a cation of smaller size involves, among others, the transformation of the Glu101 side-chain from the stable gauche(+) form to the less stable gauche(-) form. The third site is clearly described as a satellite of the CD primary site, since both sites possess common protein ligands, such as Asp53 and Glu59. Furthermore, Asp61 appears as a specific ligand of the third site in the different environments investigated in this work. We finally discuss the relevance of the third site to parvalbumin phylogeny.

Ammonia↗