Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket.

Autor:	Arroyo-Urea S; Institute for Biocomputation and Physics of Complex Systems (BIFI) and Laboratorio de Microscopías Avanzadas (LMA), University of Zaragoza, 50018, Zaragoza, Spain., Nazarova AL; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089.; Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA., Carrión-Antolí Á; Institute for Biocomputation and Physics of Complex Systems (BIFI) and Laboratorio de Microscopías Avanzadas (LMA), University of Zaragoza, 50018, Zaragoza, Spain., Bonifazi A; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States., Battiti FO; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States., Lam JH; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089.; Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA., Newman AH; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States., Katritch V; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089.; Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., García-Nafría J; Institute for Biocomputation and Physics of Complex Systems (BIFI) and Laboratorio de Microscopías Avanzadas (LMA), University of Zaragoza, 50018, Zaragoza, Spain.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Dec 19. Date of Electronic Publication: 2023 Dec 19.
DOI:	10.21203/rs.3.rs-3433207/v1
Abstrakt:	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, driven by the binding of the secondary pharmacophore to non-conserved regions of the receptor. Although bitopic ligands have great potential to improve current medications by reducing off-target side effects, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD 3 R coupled to a G O heterotrimer and bound to the D 3 R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide new 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.
Databáze:	MEDLINE
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