000145069 001__ 145069
000145069 005__ 20240926122722.0
000145069 0247_ $$2doi$$a10.1038/s41467-024-51993-4
000145069 0248_ $$2sideral$$a139862
000145069 037__ $$aART-2024-139862
000145069 041__ $$aeng
000145069 100__ $$0(orcid)0000-0003-3785-298X$$aArroyo-Urea, Sandra$$uUniversidad de Zaragoza
000145069 245__ $$aA bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site
000145069 260__ $$c2024
000145069 5060_ $$aAccess copy available to the general public$$fUnrestricted
000145069 5203_ $$aAlthough aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R:GαOβγ complex bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.
000145069 536__ $$9info:eu-repo/grantAgreement/ES/MICINN-FEDER/PID2020-113359GA-I00
000145069 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000145069 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000145069 700__ $$aNazarova, Antonina L.
000145069 700__ $$0(orcid)0000-0002-7183-2758$$aCarrión-Antolí, Ángela$$uUniversidad de Zaragoza
000145069 700__ $$aBonifazi, Alessandro
000145069 700__ $$aBattiti, Francisco O.
000145069 700__ $$aLam, Jordy Homing
000145069 700__ $$aNewman, Amy Hauck
000145069 700__ $$aKatritch, Vsevolod
000145069 700__ $$0(orcid)0000-0002-4254-3148$$aGarcía-Nafría, Javier$$uUniversidad de Zaragoza
000145069 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000145069 773__ $$g15, 1 (2024), 13 pp.$$tNature communications$$x2041-1723
000145069 8564_ $$s2973637$$uhttps://zaguan.unizar.es/record/145069/files/texto_completo.pdf$$yVersión publicada
000145069 8564_ $$s2877842$$uhttps://zaguan.unizar.es/record/145069/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000145069 909CO $$ooai:zaguan.unizar.es:145069$$particulos$$pdriver
000145069 951__ $$a2024-09-26-10:58:50
000145069 980__ $$aARTICLE