期刊
CELL
卷 177, 期 6, 页码 1495-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.04.043
关键词
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资金
- National Key R&D Program from Ministry of Science and Technology of China [2016YFA0500402]
- National Key Basic Research (973) Program from Ministry of Science and Technology of China [2015CB910101]
- National Natural Science Foundation of China [31621092, 31630017, 81861138009]
- Shirley M. Tilghman endowed professorship from Princeton University
The L-type voltage-gated Ca2+ (Ca-v) channels are modulated by various compounds exemplified by 1,4-dihydropyridines (DHP), benzothiazepines (BTZ), and phenylalkylamines (PAA), many of which have been used for characterizing channel properties and for treatment of hypertension and other disorders. Here, we report the cryoelectron microscopy (cryo-EM) structures of Ca(v)1.1 in complex with archetypal antagonistic drugs, nifedipine, diltiazem, and verapamil, at resolutions of 2.9 angstrom, 3.0 angstrom, and 2.7 angstrom, respectively, and with a DHP agonist Bay K 8644 at 2.8 angstrom. Diltiazem and verapamil traverse the central cavity of the pore domain, directly blocking ion permeation. Although nifedipine and Bay K 8644 occupy the same fenestration site at the interface of repeats III and IV, the coordination details support previous functional observations that Bay K 8644 is less favored in the inactivated state. These structures elucidate the modes of action of different Ca-v ligands and establish a framework for structure-guided drug discovery.
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