4QAC

X-RAY STRUCTURE OF ACETYLCHOLINE BINDING PROTEIN (ACHBP) IN COMPLEX WITH 4-(4-methylpiperidin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

Summary for 4QAC

• Entry DOI: 10.2210/pdb4qac/pdb
• Related: 1UV6 1UW6 1UX2 4QAA 4QAB
• Descriptor: Acetylcholine-binding protein, PHOSPHATE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: acetylcholine-binding protein
• Biological source: Lymnaea stagnalis (Great pond snail)
• Cellular location: Secreted: P58154
• Total number of polymer chains: 10
• Total formula weight: 253767.51

Authors

Kaczanowska, K.,Harel, M.,Radic, Z.,Changeux, J.-P.,Finn, M.G.,Taylor, P. (deposition date: 2014-05-03, release date: 2014-07-16, Last modification date: 2020-07-29)

Primary citation

Kaczanowska, K.,Harel, M.,Radic, Z.,Changeux, J.P.,Finn, M.G.,Taylor, P.
Structural basis for cooperative interactions of substituted 2-aminopyrimidines with the acetylcholine binding protein.
Proc.Natl.Acad.Sci.USA, 111:10749-10754, 2014

PubMed Abstract: 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.

PubMed: 25006260
DOI: 10.1073/pnas.1410992111

Experimental method

X-RAY DIFFRACTION (2.1 Å)