9BIP
Human proton sensing receptor GPR4 in complex with miniGs
Summary for 9BIP
| Entry DOI | 10.2210/pdb9bip/pdb |
| EMDB information | 44597 |
| Descriptor | miniGs, 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, ... (5 entities in total) |
| Functional Keywords | receptor, proton-sensor, g protein, signaling protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 5 |
| Total formula weight | 136166.26 |
| Authors | Howard, M.K.,Hoppe, N.,Huang, X.P.,Macdonald, C.B.,Mehrotra, E.,Rockefeller Grimes, P.,Zahm, A.M.,Trinidad, D.D.,English, J.,Coyote-Maestas, W.,Manglik, A. (deposition date: 2024-04-24, release date: 2025-01-15, Last modification date: 2025-02-19) |
| Primary citation | Howard, M.K.,Hoppe, N.,Huang, X.P.,Mitrovic, D.,Billesbolle, C.B.,Macdonald, C.B.,Mehrotra, E.,Rockefeller Grimes, P.,Trinidad, D.D.,Delemotte, L.,English, J.G.,Coyote-Maestas, W.,Manglik, A. Molecular basis of proton sensing by G protein-coupled receptors. Cell, 188:671-687.e20, 2025 Cited by PubMed Abstract: Three proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity. PubMed: 39753132DOI: 10.1016/j.cell.2024.11.036 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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