A Bitopic Agonist Bound to the Dopamine 3 Receptor Reveals a Selectivity Site

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Sep 5

PMID 39237617

Authors

Sandra Arroyo-Urea

Antonina L Nazarova

Angela Carrion-Antoli

Alessandro Bonifazi

Francisco O Battiti

Jordy Homing Lam

Amy Hauck Newman

Vsevolod Katritch

Javier Garcia-Nafria

Affiliations

Soon will be listed here.

Abstract

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 hDR:Gαβγ complex bound to the DR 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.

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