9yfu

Structure of GPR61 bound to inverse agonist compound 15

spinqualitylabelsall models 9yfu, resolution 3.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9yfu is a 4 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.08Å Ligands: A1CWB Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GPR61_HUMAN Orphan G-protein coupled receptor. Constitutively activates the G(s)-alpha/cAMP signaling pathway (PubMed:28827538). Shows a reciprocal regulatory interaction with the melatonin receptor MTNR1B most likely through receptor heteromerization (PubMed:28827538). May be involved in the regulation of food intake and body weight (By similarity).[UniProtKB:Q8C010] C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMed GPR61 is a class A orphan G protein-coupled receptor (GPCR) that is predominantly expressed in the pituitary gland and appetite-regulating centers of the brain. Genome-wide association analysis, epigenetic analysis, and animal model data have suggested that GPR61 could be a potential therapeutic target for appetite and body weight modulation. Herein, we describe our medicinal chemistry efforts in discovering a class of potent, selective, and brain-penetrant GPR61 inverse agonists. The cryogenic electron microscopy structure of GPR61 bound to compound 15 shows that this class of inverse agonists binds to an induced, intracellular, allosteric pocket and abolishes GPR61 constitutive activity by disrupting its interactions with G protein, representing a novel mode of action of GPCR inverse agonism. Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor.,Fisher EL, Dechert Schmitt AM, Tuttle JB, Unwalla R, Lovett GH, Kormos BL, Coffman KJ, Zhou D, Moran M, Williams J, Xiao J, LaChapelle EA, Fortin JP, Sheikh AQ, Stevens KA, Kong JX, Hughes EAG, Esquejo RM, Joaquim S, Amar NL, Archambault D, Garren J, Breen D, Jagarlapudi S, Dullea R, O'Connor RE, Koslov-Davino E, Callegari E, Dias JM, Lees JA, Borzilleri K, Han S, Brooks J, Vajdos FF, Goyal A, Zhang L, Zhang Y J Med Chem. 2026 Mar 15. doi: 10.1021/acs.jmedchem.6c00081. PMID:41834467 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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