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J. Biol. Chem., Vol. 283, Issue 25, 17594-17604, June 20, 2008

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Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel^*

Denis B. Tikhonov and Boris S. Zhorov¹

From the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada and the Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia

Benz(othi)azepine (BTZ) derivatives constitute one of three major classes of L-type Ca²⁺ channel ligands. Despite intensive experimental studies, no three-dimensional model of BTZ binding is available. Here we have built KvAP- and KcsA-based models of the Ca_v1.2 pore domain in the open and closed states and used multiple Monte Carlo minimizations to dock representative ligands. In our open channel model, key functional groups of BTZs interact with BTZ-sensing residues, which were identified in previous mutational experiments. The bulky tricyclic moiety occupies interface between domains III and IV, while the ammonium group protrudes into the inner pore, where it is stabilized by nucleophilic C-ends of the pore helices. In the closed channel model, contacts with several ligand-sensing residues in the inner helices are lost, which weakens ligand-channel interactions. An important feature of the ligand-binding mode in both open and closed channels is an interaction between the BTZ carbonyl group and a Ca²⁺ ion chelated by the selectivity filter glutamates in domains III and IV. In the absence of Ca²⁺, the tricyclic BTZ moiety remains in the domain interface, while the ammonium group directly interacts with a glutamate residue in the selectivity filter. Our model suggests that the Ca²⁺ potentiation involves a direct electrostatic interaction between aCa²⁺ ion and the ligand rather than an allosteric mechanism. Energy profiles indicate that BTZs can reach the binding site from the domain interface, whereas access through the open activation gate is unlikely, because reorientation of the bulky molecule in the pore is hindered.

Received for publication, January 7, 2008 , and in revised form, March 10, 2008.

^* This work was supported by a grant from the Canadian Institutes of Health Research (to B. S. Z.). Computations were performed using the facilities of the Shared Hierarchical Academic Research Computing Network. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 905-525-9140 (ext. 22049); Fax: 905-522-9033; E-mail: zhorov{at}mcmaster.ca.

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