Conformational Dynamics and Ligand Binding of the Human Voltage-Gated Proton Channel

Abstract

AbstractThe transmembrane domain of the voltage-gated proton channel (Hv1) is an ortholog of the voltage sensing domains used by many voltage-gated ion channels, except it alone can sense voltage and conduct proton. Here we characterized a nuclear magnetic resonance (NMR) structure of the wild-type human Hv1 transmembrane domain (Hv1-TM) showing that the solution structure of the human Hv1-TM is very similar to the previous crystal structure of a mouse mHv1cc chimera. Using the functional NMR sample, we performed dynamics measurement and showed that Hv1-TM in the absence of voltage displays conformational exchange consistent with small sliding movement of the S4 helix. Nuclear Overhauser enhancement spectroscopy revealed the approximate binding site of the inhibitor 2GBI. Our study demonstrates the versatility of NMR in providing comprehensive structural information on the dynamic ion channels.