| The conformational and property space of acetylcholine bound to muscarinic receptors: an entropy component accounts for the subtype selectivity of acetylcholine. | |
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MedLine Citation:
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PMID: 17544360 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The conformational behavior of receptor-bound acetylcholine (ACh) was investigated by molecular dynamics simulations. Based on the great similarity among muscarinic receptors, the study was focused on the human M(1), M(2), and M(5) receptors as previously modeled by us. The results showed that receptor-bound ACh was not frozen in a single preferred conformation but preserved an unexpected fraction of its conformational space. However, there were marked differences between the three receptors since the ligand was mostly trans in the M(1) receptor, equally distributed among trans and gauche conformers in M(2), and exclusively gauche in the M(5); the greater flexibility of M(2)-bound ACh was paralleled by the greater flexibility of the occupied M(2) binding site. By contrast, the property space of receptor-bound ACh, and particularly its virtual (computed, conformation-dependent) lipophilicity, was restricted to relatively narrow ranges optimal for successful interaction. Experimental binding investigations to the individual human M(1), M(2), and M(5) muscarinic receptors showed ACh to have a 10-fold higher affinity for the M(2) compared to the M(1) and M(5) receptors. This selectivity was not confirmed by the calculated binding scores, a fact postulated to be caused by the absence of an entropy component in such binding scores. Indeed, the Shannon entropy of all geometric and physicochemical properties monitored were markedly higher in M(2)-bound ACh compared to M(1)-bound and M(5)-bound ACh. This finding suggests that the selectivity profile of acetylcholine for the M(2) receptor is largely entropy-driven, a fact that might explain the intrinsic difficulty to design subtype-selective muscarinic agonists. |
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Authors:
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Giulio Vistoli; Alessandro Pedretti; Bernard Testa; Rosanna Matucci |
Publication Detail:
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Type: Journal Article Date: 2007-05-15 |
Journal Detail:
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Title: Archives of biochemistry and biophysics Volume: 464 ISSN: 0003-9861 ISO Abbreviation: Arch. Biochem. Biophys. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-07-30 Completed Date: 2007-10-01 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372430 Medline TA: Arch Biochem Biophys Country: United States |
Other Details:
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Languages: eng Pagination: 112-21 Citation Subset: IM |
Affiliation:
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Istituto di Chimica Farmaceutica Pietro Pratesi, Facoltà di Farmacia, Università di Milano, Viale Abruzzi 42, I-20131 Milano, Italy. Giulio.Vistoli@unimi.it |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcholine
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chemistry* Animals CHO Cells Computer Simulation Cricetinae Cricetulus Humans Kinetics Ligands Models, Chemical Models, Statistical Molecular Conformation Protein Binding Protein Conformation Receptors, Muscarinic / chemistry* |
| Chemical | |
Reg. No./Substance:
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0/Ligands; 0/Receptors, Muscarinic; 51-84-3/Acetylcholine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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