145069 20260217205555.0 doi 10.1038/s41467-024-51993-4 sideral 139862 ART-2024-139862 eng Arroyo-Urea, Sandra Universidad de Zaragoza (orcid)0000-0003-3785-298X A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site 2024 Access copy available to the general public Unrestricted Although 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. info:eu-repo/grantAgreement/ES/MICINN-FEDER/PID2020-113359GA-I00 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es 15.7 2024 MULTIDISCIPLINARY SCIENCES 10 / 136 = 0.074 2024 Q1 T1 4.761 2024 Biochemistry, Genetics and Molecular Biology (miscellaneous) 2024 Q1 Physics and Astronomy (miscellaneous) 2024 Q1 Chemistry (miscellaneous) 2024 Q1 23.4 2024 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Nazarova, Antonina L. Carrión-Antolí, Ángela Universidad de Zaragoza (orcid)0000-0002-7183-2758 Bonifazi, Alessandro Battiti, Francisco O. Lam, Jordy Homing Newman, Amy Hauck Katritch, Vsevolod García-Nafría, Javier Universidad de Zaragoza (orcid)0000-0002-4254-3148 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 15, 1 (2024), 13 pp. Nature communications 2041-1723 2973637 http://zaguan.unizar.es/record/145069/files/texto_completo.pdf Versión publicada 2877842 http://zaguan.unizar.es/record/145069/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:145069 articulos driver 2026-02-17-20:42:14 ARTICLE