Cryo-EM structures of apo and antagonist-bound human Ca v 3.1

Nature. 2019 Dec;576(7787):492-497. doi: 10.1038/s41586-019-1801-3. Epub 2019 Nov 25.

Abstract

Among the ten subtypes of mammalian voltage-gated calcium (Cav) channels, Cav3.1-Cav3.3 constitute the T-type, or the low-voltage-activated, subfamily, the abnormal activities of which are associated with epilepsy, psychiatric disorders and pain1-5. Here we report the cryo-electron microscopy structures of human Cav3.1 alone and in complex with a highly Cav3-selective blocker, Z9446,7, at resolutions of 3.3 Å and 3.1 Å, respectively. The arch-shaped Z944 molecule reclines in the central cavity of the pore domain, with the wide end inserting into the fenestration on the interface between repeats II and III, and the narrow end hanging above the intracellular gate like a plug. The structures provide the framework for comparative investigation of the distinct channel properties of different Cav subfamilies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Apoproteins / chemistry*
  • Apoproteins / genetics
  • Apoproteins / ultrastructure*
  • Binding Sites
  • Calcium Channel Blockers / chemistry*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, T-Type / chemistry*
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / ultrastructure*
  • Cryoelectron Microscopy*
  • Humans
  • Models, Molecular
  • Piperidines / chemistry*
  • Piperidines / pharmacology
  • Protein Binding
  • Protein Conformation
  • Sequence Deletion

Substances

  • Apoproteins
  • CACNA1G protein, human
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Piperidines
  • Z944