9f34
From Proteopedia
Cryo-EM structure of Dopamine 3 receptor:Go complex bound to bitopic FOB02-04A - Conformation B
Structural highlights
DiseaseGNAO_HUMAN Early infantile epileptic encephalopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAO_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(o) protein function is not clear. Stimulated by RGS14. Publication Abstract from PubMedAlthough 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 hD(3)R:Galpha(O)betagamma complex bound to the D(3)R 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. A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.,Arroyo-Urea S, Nazarova AL, Carrion-Antoli A, Bonifazi A, Battiti FO, Lam JH, Newman AH, Katritch V, Garcia-Nafria J Nat Commun. 2024 Sep 5;15(1):7759. doi: 10.1038/s41467-024-51993-4. PMID:39237617[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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