Author:
Zhao Ruiming,Kennedy Kelleigh,De Blas Gerardo A.,Orta Gerardo,Pavarotti Martín A.,Arias Rodolfo J.,de la Vega-Beltrán José Luis,Li Qufei,Dai Hui,Perozo Eduardo,Mayorga Luis S.,Darszon Alberto,Goldstein Steve A. N.
Abstract
Using a de novo peptide inhibitor, Corza6 (C6), we demonstrate that the human voltage-gated proton channel (hHv1) is the main pathway for H+ efflux that allows capacitation in sperm and permits sustained reactive oxygen species (ROS) production in white blood cells (WBCs). C6 was identified by a phage-display strategy whereby ∼1 million novel peptides were fabricated on an inhibitor cysteine knot (ICK) scaffold and sorting on purified hHv1 protein. Two C6 peptides bind to each dimeric channel, one on the S3–S4 loop of each voltage sensor domain (VSD). Binding is cooperative with an equilibrium affinity (Kd) of ∼1 nM at −50 mV. As expected for a VSD-directed toxin, C6 inhibits by shifting hHv1 activation to more positive voltages, slowing opening and speeding closure, effects that diminish with membrane depolarization.
Funder
HHS | NIH | National Institute of General Medical Sciences
United States - Israel Binational Science Foundation
MINCyT | ANPCyT | Fondo para la Investigación Científica y Tecnológica
Consejo Nacional de Investigaciones Científicas y Técnicas
Universidad Nacional de Cuyo
Publisher
Proceedings of the National Academy of Sciences
Cited by
48 articles.
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