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Structural insights into TRPV2 activation by small molecules

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dc.contributor.authorPumroy, Ruth A.
dc.contributor.authorProtopopova, Anna D.
dc.contributor.authorFricke, Tabea C.
dc.contributor.authorLange, Iris U.
dc.contributor.authorHaug, Ferdinand M.
dc.contributor.authorNguyen, Phuong T.
dc.contributor.authorGallo, Pamela N.
dc.contributor.authorSousa, Bárbara B.
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorYarov-Yarovoy, Vladimir
dc.contributor.authorLeffler, Andreas
dc.contributor.authorMoiseenkova-Bell, Vera Y.
dc.date.accessioned2022-05-03T13:53:47Z
dc.date.available2022-05-03T13:53:47Z
dc.date.issued2022
dc.description© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.pt_PT
dc.description.abstractTransient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators.pt_PT
dc.description.sponsorshipThis work was supported by grants from the National Institute of Health (R01GM103899 and R01GM129357 to V.Y.M.-B.), from the Royal Society (URF\R\180019 to G.J.L.B.), from FCT Portugal (FCT Investigator, IF/00624/2015 to G.J.L.B., SFRH/BPD/143583/2019 to B.B.S.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2022 Apr 28;13(1):2334pt_PT
dc.identifier.doi10.1038/s41467-022-30083-3pt_PT
dc.identifier.eissn2041-1723
dc.identifier.urihttp://hdl.handle.net/10451/52650
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationSFRH/BPD/143583/2019pt_PT
dc.relationModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
dc.relation.publisherversionhttps://www.nature.com/ncomms/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleStructural insights into TRPV2 activation by small moleculespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberIF/00624/2015/CP1287/CT0002
oaire.awardTitleModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00624%2F2015%2FCP1287%2FCT0002/PT
oaire.citation.issue1pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume13pt_PT
oaire.fundingStreamInvestigador FCT
person.familyNameBernardes
person.givenNameGonçalo
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id14046757500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isAuthorOfPublication.latestForDiscoveryd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isProjectOfPublicationbb7a22d9-03ef-4ef0-9dec-48a87c479e66
relation.isProjectOfPublication.latestForDiscoverybb7a22d9-03ef-4ef0-9dec-48a87c479e66

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