9YFU
Structure of GPR61 bound to inverse agonist compound 15
This is a non-PDB format compatible entry.
Summary for 9YFU
| Entry DOI | 10.2210/pdb9yfu/pdb |
| EMDB information | 72906 |
| Descriptor | G-protein coupled receptor 61,Soluble cytochrome b562, Fab24 BAK5 heavy chain, Hinge-binding nanobody, ... (6 entities in total) |
| Functional Keywords | gpcr, gpr61, orphan receptor, inverse agonist, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 128179.26 |
| Authors | |
| Primary citation | Fisher, E.L.,Dechert Schmitt, A.M.,Tuttle, J.B.,Unwalla, R.,Lovett, G.H.,Kormos, B.L.,Coffman, K.J.,Zhou, D.,Moran, M.,Williams, J.,Xiao, J.,LaChapelle, E.A.,Fortin, J.P.,Sheikh, A.Q.,Stevens, K.A.,Kong, J.X.,Hughes, E.A.G.,Esquejo, R.M.,Joaquim, S.,Amar, N.L.,Archambault, D.,Garren, J.,Breen, D.,Jagarlapudi, S.,Dullea, R.,O'Connor, R.E.,Koslov-Davino, E.,Callegari, E.,Dias, J.M.,Lees, J.A.,Borzilleri, K.,Han, S.,Brooks, J.,Vajdos, F.F.,Goyal, A.,Zhang, L.,Zhang, Y. Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor. J.Med.Chem., 2026 Cited by PubMed Abstract: 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 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. PubMed: 41834467DOI: 10.1021/acs.jmedchem.6c00081 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.08 Å) |
Structure validation
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