6JPB

Rabbit Cav1.1-Diltiazem Complex

Summary for 6JPB

• Entry DOI: 10.2210/pdb6jpb/pdb
• EMDB information: 9869
• Descriptor: Voltage-dependent L-type calcium channel subunit alpha-1S, CALCIUM ION, 1,2-Distearoyl-sn-glycerophosphoethanolamine, ... (14 entities in total)
• Functional Keywords: membrane protein complex modulated by fda approved drug., membrane protein
• Biological source: Oryctolagus cuniculus (Rabbit); More
• Total number of polymer chains: 5
• Total formula weight: 473151.15

Authors

Zhao, Y.,Huang, G.,Wu, J.,Yan, N. (deposition date: 2019-03-26, release date: 2019-06-12, Last modification date: 2024-11-13)

Primary citation

Zhao, Y.,Huang, G.,Wu, J.,Wu, Q.,Gao, S.,Yan, Z.,Lei, J.,Yan, N.
Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+Channel.
Cell, 177:1495-1506.e12, 2019

PubMed Abstract: The L-type voltage-gated Ca (Ca) 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 Ca1.1 in complex with archetypal antagonistic drugs, nifedipine, diltiazem, and verapamil, at resolutions of 2.9 Å, 3.0 Å, and 2.7 Å, respectively, and with a DHP agonist Bay K 8644 at 2.8 Å. 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 ligands and establish a framework for structure-guided drug discovery.

PubMed: 31150622
DOI: 10.1016/j.cell.2019.04.043

Experimental method

ELECTRON MICROSCOPY (2.9 Å)