On the role of water density fluctuations in the inhibition of a proton channel

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Abstract
Significance: Hv1, a voltage-gated proton channel, is an emerging pharmacological target implicated in many pathological conditions, including cancer and ischemic brain damage. We used the recently published experimental structure of Hv1 to generate structural models of relevant conformational states. Thermodynamic analyses of pore waters shed light on the molecular underpinnings of Hv1 druggability. We exploit this information to suggest possible optimizations of known inhibitors and identify a potential binding site located at the exit of the proton path. The resulting molecular picture paves the way for the discovery of novel Hv1 inhibitors and outlines a general approach for identifying druggable binding sites in ion channels.
Funding Information
  • HHS | NIH | National Institute of General Medical Sciences (P01 GM55876)
  • National Science Foundation (ACI-1614804)
  • EC | European Research Council (PIOF-GA-2012-329534)
  • National Science Foundation (CNS-09-58854)

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