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However, few H<jats:sub>V<\/jats:sub>1 channel antagonists have been reported. Here, we have identified a novel H<jats:sub>V<\/jats:sub>1 channel antagonist from scorpion venom and have elucidated its action mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>H<jats:sub>V<\/jats:sub>1 and NaV channels were heterologously expressed in mammalian cell lines and their currents recorded using whole\u2010cell patch clamp. Site\u2010directed mutagenesis was used to generate mutants. Toxins were recombinantly produced in <jats:italic>Escherichia coli.<\/jats:italic> AGAP\/W38F\u2010H<jats:sub>V<\/jats:sub>1 interaction was modelled by molecular dynamics simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The scorpion toxin AGAP (anti\u2010tumour analgesic peptide) potently inhibited H<jats:sub>V<\/jats:sub>1 currents. One AGAP mutant has reduced Na<jats:sub>V<\/jats:sub> channel activity but intact H<jats:sub>V<\/jats:sub>1 activity (AGAP\/W38F). AGAP\/W38F inhibited H<jats:sub>V<\/jats:sub>1 channel activation by trapping its S4 voltage sensor in a deactivated state and inhibited H<jats:sub>V<\/jats:sub>1 currents with less pH dependence than Zn<jats:sup>2+<\/jats:sup>. Mutation analysis showed that the binding pockets of AGAP\/W38F and Zn<jats:sup>2+<\/jats:sup> in H<jats:sub>V<\/jats:sub>1 channel partly overlapped (common sites are His140 and His193). The E153A mutation at the intracellular Coulombic network (ICN) in H<jats:sub>V<\/jats:sub>1 channel markedly reduced AGAP\/W38F inhibition, as observed for Zn<jats:sup>2+<\/jats:sup>. Experimental data and MD simulations suggested that AGAP\/W38F inhibited H<jats:sub>V<\/jats:sub>1 channel using a Zn<jats:sup>2+<\/jats:sup>\u2010like long\u2010range conformational coupling mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our results suggest that the Zn<jats:sup>2+<\/jats:sup> binding pocket in H<jats:sub>V<\/jats:sub>1 channel might be a hotspot for modulators and valuable for designing H<jats:sub>V<\/jats:sub>1 channel ligands. Moreover, AGAP\/W38F is a useful molecular probe to study H<jats:sub>V<\/jats:sub>1 channel and a lead compound for drug development.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14984","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T07:19:51Z","timestamp":1579850391000},"page":"2351-2364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Scorpion toxin inhibits the voltage\u2010gated proton channel using a Zn<sup>2+<\/sup>\u2010like long\u2010range conformational coupling mechanism"],"prefix":"10.1111","volume":"177","author":[{"given":"Dongfang","family":"Tang","sequence":"first","affiliation":[{"name":"The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences Hunan Normal University  Changsha 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