9F33

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

This is a non-PDB format compatible entry.

Summary for 9F33

• Entry DOI: 10.2210/pdb9f33/pdb
• EMDB information: 50168
• Descriptor: Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, dopamine, bitopic, receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 191428.30

Authors

Arroyo-Urea, S.,Garcia-Nafria, J. (deposition date: 2024-04-24, release date: 2024-09-18, Last modification date: 2024-10-16)

Primary citation

Arroyo-Urea, S.,Nazarova, A.L.,Carrion-Antoli, A.,Bonifazi, A.,Battiti, F.O.,Lam, J.H.,Newman, A.H.,Katritch, V.,Garcia-Nafria, J.
A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.
Nat Commun, 15:7759-7759, 2024

PubMed 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.

PubMed: 39237617
DOI: 10.1038/s41467-024-51993-4

Experimental method

ELECTRON MICROSCOPY (3.05 Å)