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Structural basis for cooperative interactions of substituted 2-aminopyrimidines with the acetylcholine binding protein.
Kaczanowska, Katarzyna; Harel, Michal; Radic, Zoran; Changeux, Jean-Pierre; Finn, M G; Taylor, Palmer.
Affiliation
  • Kaczanowska K; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
  • Harel M; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
  • Radic Z; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
  • Changeux JP; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;Centre National de la Recherche Scientifique, Unité de Recherche Associée 2182, Institut Pasteur F-75015 Paris and Collège de France, F-75005 Paris, France; and
  • Finn MG; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
  • Taylor P; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093; changeux@noos.fr pwtaylor@ucsd.edu.
Proc Natl Acad Sci U S A ; 111(29): 10749-54, 2014 Jul 22.
Article in En | MEDLINE | ID: mdl-25006260
The nicotinic acetylcholine receptor (nAChR) and the acetylcholine binding protein (AChBP) are pentameric oligomers in which binding sites for nicotinic agonists and competitive antagonists are found at selected subunit interfaces. The nAChR spontaneously exists in multiple conformations associated with its activation and desensitization steps, and conformations are selectively stabilized by binding of agonists and antagonists. In the nAChR, agonist binding and the associated conformational changes accompanying activation and desensitization are cooperative. AChBP, which lacks the transmembrane spanning and cytoplasmic domains, serves as a homology model of the extracellular domain of the nAChRs. We identified unique cooperative binding behavior of a number of 4,6-disubstituted 2-aminopyrimidines to Lymnaea AChBP, with different molecular variants exhibiting positive, nH > 1.0, and negative cooperativity, nH < 1.0. Therefore, for a distinctive set of ligands, the extracellular domain of a nAChR surrogate suffices to accommodate cooperative interactions. X-ray crystal structures of AChBP complexes with examples of each allowed the identification of structural features in the ligands that confer differences in cooperative behavior. Both sets of molecules bind at the agonist-antagonist site, as expected from their competition with epibatidine. An analysis of AChBP quaternary structure shows that cooperative ligand binding is associated with a blooming or flare conformation, a structural change not observed with the classical, noncooperative, nicotinic ligands. Positively and negatively cooperative ligands exhibited unique features in the detailed binding determinants and poses of the complexes.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Carrier Proteins Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2014 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Carrier Proteins Limits: Animals Language: En Journal: Proc Natl Acad Sci U S A Year: 2014 Document type: Article Country of publication: United States