9f33

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

spinqualitylabelsall models 9f33, resolution 3.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9f33 is a 5 chain structure with sequence from Aequorea victoria, Homo sapiens, Mus musculus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.05Å Ligands: A1H9N Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBG2_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). Publication Abstract from PubMed 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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