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Gen. Physiol."],"published-print":{"date-parts":[[2019,3,4]]},"abstract":"<jats:p>Allosteric ligands modulate protein activity by altering the energy landscape of                    conformational space in ligand\u2013protein complexes. Here we investigate how                    ligand binding to a K<jats:sup>+<\/jats:sup> channel\u2019s voltage sensor allosterically                    modulates opening of its K<jats:sup>+<\/jats:sup>-conductive pore. The tarantula venom                    peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat                    voltage-gated K<jats:sup>+<\/jats:sup> (Kv) channel Kv2.1 and acts as a partial inverse                    agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more                    rapidly, and requires more positive voltage to reach the same                    K<jats:sup>+<\/jats:sup>-conductance as the unbound channel. Further, activation kinetics                    are more sigmoidal, indicating that multiple conformational changes coupled to                    opening are modulated. Single-channel current amplitudes reveal that each                    channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1                    channels by GxTx results from decreased open probability due to increased                    occurrence of long-lived closed states; the time constant of the final pore                    opening step itself is not impacted by GxTx. When intracellular potential is                    less than 0 mV, GxTx traps the gating charges on Kv2.1\u2019s voltage sensors                    in their most intracellular position. Gating charges translocate at positive                    voltages, however, indicating that GxTx stabilizes the most intracellular                    conformation of the voltage sensors (their resting conformation). Kinetic                    modeling suggests a modulatory mechanism: GxTx reduces the probability of                    voltage sensors activating, giving the pore opening step less frequent                    opportunities to occur. This mechanism results in K<jats:sup>+<\/jats:sup>-conductance                    activation kinetics that are voltage-dependent, even if pore opening (the                    rate-limiting step) has no inherent voltage dependence. We conclude that GxTx                    stabilizes voltage sensors in a resting conformation, and inhibits K<jats:sup>+<\/jats:sup>                    currents by limiting opportunities for the channel pore to open, but has little,                    if any, direct effect on the microscopic kinetics of pore opening. The impact of                    GxTx on channel gating suggests that Kv2.1\u2019s pore opening step does not                    involve movement of its voltage sensors.<\/jats:p>","DOI":"10.1085\/jgp.201812213","type":"journal-article","created":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T10:05:12Z","timestamp":1541412312000},"page":"292-315","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["The tarantula toxin GxTx detains K<sup>+<\/sup> channel gating charges                    in their resting conformation"],"prefix":"10.1085","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5616-2661","authenticated-orcid":true,"given":"Drew C.","family":"Tilley","sequence":"first","affiliation":[{"name":"Department of Physiology & Membrane Biology, University of                    California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9217-3069","authenticated-orcid":true,"given":"Juan M.","family":"Angueyra","sequence":"additional","affiliation":[{"name":"Neurobiology Course, Marine Biological Laboratory, Woods Hole,                    MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Eum","sequence":"additional","affiliation":[{"name":"Department of Physiology & Membrane Biology, University of                    California, Davis, Davis, CA"},{"name":"Neurobiology Course, Marine Biological Laboratory, Woods Hole,                    MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heesoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Neurobiology Course, Marine Biological Laboratory, Woods Hole,                    MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-4148","authenticated-orcid":true,"given":"Luke H.","family":"Chao","sequence":"additional","affiliation":[{"name":"Neurobiology Course, Marine Biological Laboratory, Woods Hole,                    MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-6779","authenticated-orcid":true,"given":"Anthony W.","family":"Peng","sequence":"additional","affiliation":[{"name":"Neurobiology Course, Marine Biological Laboratory, Woods Hole,                    MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6975-982X","authenticated-orcid":true,"given":"Jon T.","family":"Sack","sequence":"additional","affiliation":[{"name":"Department of Physiology & Membrane Biology, University of                    California, Davis, Davis, CA"},{"name":"Neurobiology Course, Marine Biological Laboratory, Woods Hole,                    MA"},{"name":"Department of Anesthesiology and Pain Medicine, University of                    California, Davis, Davis, 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