Role of hydrophobicity in the binding of coenzymes

Janin, Joël; Chothia, Cyrus

doi:10.1021/bi00608a001

Cited by 188 publications

(137 citation statements)

References 33 publications

(47 reference statements)

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“…Neither toxin loop I nor loop III interact with the receptor, which is in agreement with our mutational data (7). Although 75% of the surface of the toxin remains outside the complex, the buried surface is equal to 2,450 Å 2 , as observed for typical protein-protein interactions (23,24). Viewed perpendicularly to the 5-fold axis of the pentamer, the toxin lies equatorially to the extracellular domain, with its concave side facing the viewer with loops I and III orientated toward the top and bottom of the receptor domain, respectively (Fig.…”

Section: Docking Of ␣-Cbtx On a Model Of ␣7supporting

confidence: 88%

Experimentally based model of a complex between a snake toxin and the α7 nicotinic receptor

Fruchart-Gaillard

Gilquin

Antil-Delbeke

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

120

150

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To understand how snake neurotoxins interact with nicotinic acetylcholine receptors, we have elaborated an experimentally based model of the ␣-cobratoxin-␣7 receptor complex. This model was achieved by using (i) a three-dimensional model of the ␣7 extracellular domain derived from the crystallographic structure of the homologous acetylcholine-binding protein, (ii) the previously solved x-ray structure of the toxin, and (iii) nine pairs of residues identified by cycle-mutant experiments to make contacts between the ␣-cobratoxin and ␣7 receptor. Because the receptor loop F occludes entrance of the toxin binding pocket, we submitted this loop to a dynamics simulation and selected a conformation that allowed the toxin to reach its binding site. T he ␣-neurotoxins from snake venom are potent antagonists that block nicotinic acetylcholine receptors (AChRs) and hence affect synaptic transmission (1-3). Despite many studies (reviewed in ref. 4), the molecular process associated with this efficient blockage remains unclear. To approach this question, we previously studied ␣-cobratoxin (␣-Cbtx), an ␣͞K neurotoxin that binds to both muscular and homopentameric neuronal receptors (␣7 and ␣8) with high affinities (4). This toxin, similar to other snake neurotoxins, is folded into three adjacent loops rich in ␤-sheet that emerge from a small globular core in which four disulfide bonds are located (5). By mutational analyses, the residues by which ␣-Cbtx interacts with the muscular-type or neuronal ␣7 receptors were identified previously (6, 7). The present study shows how functional residues account for the antagonistic properties of the toxin toward the ␣7 neuronal receptor. The ␣7 AChR possesses five identical ␣7 subunits (8) that offer five ligand-binding sites located at the interface of two subunits (9). These sites include residues located on the different functional loops described previously on the principal ␣7 (ϩ) face, loops A, B, and C and on the complementary ␣7 (Ϫ) face, loops D, E, and F (refs. 10-13; see Fig. 1). Until now, the residues of the ␣7 receptor involved in snake toxin binding have remained unknown.The aim of the present paper is fourfold. First, by an extensive mutational study we have identified ␣7 receptor residues involved in the interaction with ␣-Cbtx. Second, by using a double-mutant cycle approach we have disclosed several pairs of interacting residues in the toxin-receptor complex. Third, by using the three-dimensional (3D) structure of an AChBP that is similar functionally and structurally to the N-terminal domain of an AChR ␣-subunit (14), we used a 3D model for the ␣7 subunit extracellular region obtained by comparative modeling [see accompanying paper on page 3210 (15)]. Fourth, by using this model, a molecular dynamics simulation of the loop F region, and the constraints derived from our pairwise analysis, we propose an experimentally based 3D model of the complex between the ␣-Cbtx and ␣7 receptor, which explains the antagonistic properties of the snake toxin toward the neuronal recepto...

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Section: Docking Of ␣-Cbtx On a Model Of ␣7supporting

confidence: 88%

Experimentally based model of a complex between a snake toxin and the α7 nicotinic receptor

Fruchart-Gaillard

Gilquin

Antil-Delbeke

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

120

150

View full text Add to dashboard Cite

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“…We analyze their geometric and chemical properties and attempt to draw general rules from the comparison. We confirm rules derived many years ago from analysis of only a handful of X-ray structures (Chothia & Janin, 1975;Janin & Chothia, 1990) and add some new ones (Lo Conte et al, 1999), trusting that this trend will hold as more data shed further light on aspects of protein-protein recognition that still lack a structural basis.…”

Section: Diversity Of Protein-protein Recognitionsupporting

confidence: 81%

Macromolecular recognition in the Protein Data Bank

Janin

Rodier

Chakrabarti

et al. 2006

Acta Crystallogr D Biol Cryst

101

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Crystal structures deposited in the Protein Data Bank illustrate the diversity of biological macromolecular recognition: transient interactions in protein-protein and protein-DNA complexes and permanent assemblies in homodimeric proteins. The geometric and physical chemical properties of the macromolecular interfaces that may govern the stability and specificity of recognition are explored in complexes and homodimers compared with crystal-packing interactions. It is found that crystal-packing interfaces are usually much smaller; they bury fewer atoms and are less tightly packed than in specific assemblies. Standard-size interfaces burying 1200-2000 Å 2 of protein surface occur in protease-inhibitor and antigen-antibody complexes that assemble with little or no conformation changes. Short-lived electron-transfer complexes have small interfaces; the larger size of the interfaces observed in complexes involved in signal transduction and homodimers correlates with the presence of conformation changes, often implicated in biological function. Results of the CAPRI (critical assessment of predicted interactions) blind prediction experiment show that docking algorithms efficiently and accurately predict the mode of assembly of proteins that do not change conformation when they associate. They perform less well in the presence of large conformation changes and the experiment stimulates the development of novel procedures that can handle such changes.

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“…Although additional evidence concerning dimerization has not been obtained, the extensive and conserved nature of this interaction is intriguing. The buried molecular surface area for a monomer upon dimerization is 1566 ,~2, a value typical for biologically relevant protein-protein interactions (Janin & Chothia, 1990). The structures suggest that dimerization could be an additional mechanism for inhibiting the enzyme.…”

Section: Resultsmentioning

confidence: 91%

Crystallographic studies of casein kinase I δ: toward a structural understanding of auto-inhibition

Longenecker

Roach

Hurley

1998

Acta Crystallogr D Biol Cryst

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A recombinant form of mammalian casein kinase I (CKI3) containing the catalytic domain and an autoinhibitory domain was expressed in Escherichia coli, purified and crystallized. X-ray data were collected to 2.4~, rcsolution, and the crystals belong to space group C2221. Molecular replacement using the structure of the catalytic domain of CKI3 yielded strong electron density for residues in the model, but no interpretable density was found for the inhibitory domain. A conserved intermolecular contact suggests the formation of dimers which would inhibit the activity of this protein kinase.

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Role of hydrophobicity in the binding of coenzymes

Cited by 188 publications

References 33 publications

Experimentally based model of a complex between a snake toxin and the α7 nicotinic receptor

Experimentally based model of a complex between a snake toxin and the α7 nicotinic receptor

Macromolecular recognition in the Protein Data Bank

Crystallographic studies of casein kinase I δ: toward a structural understanding of auto-inhibition

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