Structural basis for Ca2+ selectivity of a voltage-gated calcium channel

Nature. 2014 Jan 2;505(7481):56-61. doi: 10.1038/nature12775. Epub 2013 Nov 24.


Voltage-gated calcium (CaV) channels catalyse rapid, highly selective influx of Ca(2+) into cells despite a 70-fold higher extracellular concentration of Na(+). How CaV channels solve this fundamental biophysical problem remains unclear. Here we report physiological and crystallographic analyses of a calcium selectivity filter constructed in the homotetrameric bacterial NaV channel NaVAb. Our results reveal interactions of hydrated Ca(2+) with two high-affinity Ca(2+)-binding sites followed by a third lower-affinity site that would coordinate Ca(2+) as it moves inward. At the selectivity filter entry, Site 1 is formed by four carboxyl side chains, which have a critical role in determining Ca(2+) selectivity. Four carboxyls plus four backbone carbonyls form Site 2, which is targeted by the blocking cations Cd(2+) and Mn(2+), with single occupancy. The lower-affinity Site 3 is formed by four backbone carbonyls alone, which mediate exit into the central cavity. This pore architecture suggests a conduction pathway involving transitions between two main states with one or two hydrated Ca(2+) ions bound in the selectivity filter and supports a 'knock-off' mechanism of ion permeation through a stepwise-binding process. The multi-ion selectivity filter of our CaVAb model establishes a structural framework for understanding the mechanisms of ion selectivity and conductance by vertebrate CaV channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Binding Sites
  • Biocatalysis
  • Calcium / metabolism
  • Calcium Channels / chemistry*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cations, Divalent / metabolism
  • Crystallography, X-Ray
  • Electric Conductivity
  • Ion Channel Gating*
  • Models, Biological
  • Models, Molecular
  • Structure-Activity Relationship
  • Substrate Specificity


  • Bacterial Proteins
  • Calcium Channels
  • Cations, Divalent
  • Calcium

Associated data

  • PDB/4MS2
  • PDB/4MTF
  • PDB/4MTG
  • PDB/4MTO
  • PDB/4MVM
  • PDB/4MVO
  • PDB/4MVQ
  • PDB/4MVR
  • PDB/4MVS
  • PDB/4MVU
  • PDB/4MVZ
  • PDB/4MW3
  • PDB/4MW8