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For particular applications, genetically-encoded HVACC blockers may enable channel inhibition with greater tissue-specificity and versatility than is achievable with small molecules. Here, we engineered a genetically-encoded HVACC inhibitor by first isolating an immunized llama nanobody (nb.F3) that binds auxiliary HVACC CaV\u03b2 subunits. Nb.F3 by itself is functionally inert, providing a convenient vehicle to target active moieties to CaV\u03b2-associated channels. Nb.F3 fused to the catalytic HECT domain of Nedd4L (CaV-a\u03b2lator), an E3 ubiquitin ligase, ablated currents from diverse HVACCs reconstituted in HEK293 cells, and from endogenous CaV1\/CaV2 channels in mammalian cardiomyocytes, dorsal root ganglion neurons, and pancreatic \u03b2 cells. In cardiomyocytes, CaV-a\u03b2lator redistributed CaV1.2 channels from dyads to Rab-7-positive late endosomes. This work introduces CaV-a\u03b2lator as a potent genetically-encoded HVACC inhibitor, and describes a general approach that can be broadly adapted to generate versatile modulators for macro-molecular membrane protein complexes.<\/jats:p>","DOI":"10.7554\/elife.49253","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T08:00:19Z","timestamp":1565596819000},"source":"Crossref","is-referenced-by-count":45,"title":["A potent voltage-gated calcium channel inhibitor engineered from a nanobody targeted to auxiliary CaV\u03b2 subunits"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-8470","authenticated-orcid":true,"given":"Travis J","family":"Morgenstern","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Columbia University, Vagelos College of Physicians and Surgeons, New York, United 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