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| - | [[Image:2pgz.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2pgz| PDB=2pgz | SCENE= }} | | {{STRUCTURE_2pgz| PDB=2pgz | SCENE= }} |
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| - | '''Crystal structure of Cocaine bound to an ACh-Binding Protein'''
| + | ===Crystal structure of Cocaine bound to an ACh-Binding Protein=== |
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| - | ==Overview==
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| - | Rapid neurotransmission is mediated through a superfamily of Cys-loop receptors that includes the nicotinic acetylcholine (nAChR), gamma-aminobutyric acid (GABA(A)), serotonin (5-HT(3)) and glycine receptors. A class of ligands, including galanthamine, local anesthetics and certain toxins, interact with nAChRs non-competitively. Suggested modes of action include blockade of the ion channel, modulation from undefined extracellular sites, stabilization of desensitized states, and association with annular or boundary lipid. Alignment of mammalian Cys-loop receptors shows aromatic residues, found in the acetylcholine or ligand-binding pocket of nAChRs, are conserved in all subunit interfaces of neuronal nAChRs, including those that are not formed by alpha subunits on the principal side of the transmitter binding site. The amino-terminal domain containing the ligand recognition site is homologous to the soluble acetylcholine-binding protein (AChBP) from mollusks, an established structural and functional surrogate. We assess ligand specificity and employ X-ray crystallography with AChBP to demonstrate ligand interactions at subunit interfaces lacking vicinal cysteines (i.e. the non-alpha subunit interfaces in nAChRs). Non-competitive nicotinic ligands bind AChBP with high affinity (K(d) 0.015-6 microM). We mutated the vicinal cysteine residues in loop C of AChBP to mimic the non-alpha subunit interfaces of neuronal nAChRs and other Cys loop receptors. Classical nicotinic agonists show a 10-40-fold reduction in binding affinity, whereas binding of ligands known to be non-competitive are not affected. X-ray structures of cocaine and galanthamine bound to AChBP (1.8 A and 2.9 A resolution, respectively) reveal interactions deep within the subunit interface and the absence of a contact surface with the tip of loop C. Hence, in addition to channel blocking, non-competitive interactions with heteromeric neuronal nAChR appear to occur at the non-alpha subunit interface, a site presumed to be similar to that of modulating benzodiazepines on GABA(A) receptors.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_17481657}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 17481657 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_17481657}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Nicotinic acetycholine receptor]] | | [[Category: Nicotinic acetycholine receptor]] |
| | [[Category: Non-competitive inhibitor]] | | [[Category: Non-competitive inhibitor]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 13:05:41 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 09:58:47 2008'' |
Revision as of 06:58, 29 July 2008
Template:STRUCTURE 2pgz
Crystal structure of Cocaine bound to an ACh-Binding Protein
Template:ABSTRACT PUBMED 17481657
About this Structure
2PGZ is a Single protein structure of sequence from Aplysia californica. Full crystallographic information is available from OCA.
Reference
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors., Hansen SB, Taylor P, J Mol Biol. 2007 Jun 15;369(4):895-901. Epub 2007 Mar 31. PMID:17481657
Page seeded by OCA on Tue Jul 29 09:58:47 2008
