EMD-50169

Single-particle
3.09 Å
EMD-50169 Deposition: 24/04/2024
Map released: 18/09/2024
Last modified: 20/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-50169

Cryo-EM structure of Dopamine 3 receptor:Go complex bound to bitopic FOB02-04A - Conformation B

EMD-50169

Single-particle
3.09 Å
EMD-50169 Deposition: 24/04/2024
Map released: 18/09/2024
Last modified: 20/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Rattus norvegicus, Mus musculus
Sample: D3R: Gtrimer: scFv16 complex bound to the bitopic FOB02-04A - Conformation B
Fitted models: 9f34 (Avg. Q-score: 0.456)

Deposition Authors: Arroyo-Urea S , Garcia-Nafria J
A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.
PUBMED: 39237617
DOI: doi:10.1038/s41467-024-51993-4
ISSN: 2041-1723
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 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.