Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+ Channel

Abstract

The L-type voltage-gated Ca 2+ (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 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 v ligands and establish a framework for structure-guided drug discovery.

4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action

“…Our data coincide with the conception of [43] on calcium channel agonists and antagonist. Identical accommodation sites for nifedipine and Bay K8644 were postulated [43]. However, if the concentration of DHP agonists is high enough to overcome the energetic barrier, the dissociation of agonistic ligands and inactivated channel would be prevented; in that case, the agonists could function as antagonists [43].…”

“…It is further planned to use cardiomyocyte cell cultures and/or cardiac tissues for elucidating the mode of action of compound 4, because it has been shown that the characteristics of the DHP derivatives, the tissue properties, and the types of stimuli are all relevant to the calcium channel modulation [42]. Our data coincide with the conception of [43] on calcium channel agonists and antagonist. Identical accommodation sites for nifedipine and Bay K8644 were postulated [43].…”

Structural basis for pore blockade of the human cardiac sodium channel Nav1.5 by tetrodotoxin and quinidine

“…The two structures will hereafter be referred to as Nav1.5T and Nav1.5Q for complexes with TTX and quinidine, respectively. Unlike Cav1.1 and Cav3.1, which undergo main chain shift of the pore-forming S6 segments when binding to pore blockers such as diltiazem, verapamil, and Z944 (22,23), the two structures of Nav1.5 remain nearly identical the root-mean-square deviation (RMSD) of 0.16 Å over 771 Cα atoms ( Figure 2A).…”

Regulatory mechanisms of ryanodine receptor/Ca2+ release channel revealed by recent advancements in structural studies

“…Recently cryo-EM structures of rabbit DHPR have been determined at near-atomic resolution Zhao et al 2019). All five subunits were resolved and the molecular structure was well understood.…”