Publication: Homology model of dihydropyridine receptor: implications for L-type Ca(2+) channel modulation by agonists and antagonists

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Title	Homology model of dihydropyridine receptor: implications for L-type Ca(2+) channel modulation by agonists and antagonists
Authors/Editors*	Zhorov BS, Folkman EV, Ananthanarayanan VS.
Where published*	Arch Biochem Biophys
How published*	Journal
Year*	2001
Volume	393
Number	1
Pages	22-41
Publisher
Keywords
Link	http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11516158&query_hl=1&itool=pubmed_docsum
Abstract	L-type calcium channels (LCCs) are transmembrane (TM) proteins that respond to membrane depolarization by selectively permeating Ca(2+) ions. Dihydropyridine (DHP) agonists and antagonist modulate Ca(2+) permeation by stabilizing, respectively, the open and closed states of the channel. The mechanism of action of these drugs remains unclear. Using, as a template, the crystal structure of the KcsA K(+) channel (Doyle et al. (1998) Science 280, 69-77), we have built several homology models of LCC with alternative alignments of TM segments between the proteins. In each model, nifedipine was docked in the pore region and in the interface between repeats III and IV. Several starting structures were generated by constraining the ligand to residues whose mutations reportedly affect DHP binding (DHP-sensing residues). These structures were Monte Carlo-minimized with and without constraints. In the complex with the maximum number of contacts between the ligand and DHP-sensing residues and the lowest ligand-receptor energy, the drug fits snugly in the