Structure of the voltage-gated calcium channel Cav1.1 at 3.6 Å resolution

The voltage-gated calcium (Ca v ) channels convert membrane electrical signals to intracellular Ca 2+ -mediated events. Among the ten subtypes of Ca v channel in mammals, Ca v 1.1 is specified for the excitation–contraction coupling of skeletal muscles. Here we present the cryo-electron microscopy structure of the rabbit Ca v 1.1 complex at a nominal resolution of 3.6 Å. The inner gate of the ion-conducting α1-subunit is closed and all four voltage-sensing domains adopt an ‘up’ conformation, suggesting a potentially inactivated state. The extended extracellular loops of the pore domain, which are stabilized by multiple disulfide bonds, form a windowed dome above the selectivity filter. One side of the dome provides the docking site for the α2δ-1-subunit, while the other side may attract cations through its negative surface potential. The intracellular I–II and III–IV linker helices interact with the β 1a -subunit and the carboxy-terminal domain of α1, respectively. Classification of the particles yielded two additional reconstructions that reveal pronounced displacement of β 1a and adjacent elements in α1. The atomic model of the Ca v 1.1 complex establishes a foundation for mechanistic understanding of excitation–contraction coupling and provides a three-dimensional template for molecular interpretations of the functions and disease mechanisms of Ca v and Na v channels. The cryo-electron microscopy structure of the rabbit voltage-gated calcium channel Ca v 1.1 complex at a nominal resolution of 3.6 ångströms. A eukaryotic Ca v channel at near-atomic resolution Voltage-gated calcium (Ca v ) channels translate membrane electrical signals into intracellular Ca 2+ -mediated events. For example, Ca v 1.1 is expressed in skeletal muscle and serves as the voltage sensor for excitation–contraction coupling. These authors report a 3.6 Å resolution cryo-electron microscopy structure of rabbit Ca v 1.1. The high resolution of the core ɑ1-subunit makes it possible to examine the ion permeation path in detail, and the structure reveals that several extended extracellular loops unexpectedly form a 'windowed dome' above the selectivity filter. The near-atomic structure of Ca v 1.1 complex establishes a foundation for mechanistic understanding of excitation–contraction coupling and provides a three-dimensional template for molecular interpretations of function and disease mechanism of Ca v and Na v channels.