7YK6

Cryo-EM structure of the compound 4-bound human relaxin family peptide receptor 4 (RXFP4)-Gi complex

Summary for 7YK6

• Entry DOI: 10.2210/pdb7yk6/pdb
• EMDB information: 33888
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-2, Relaxin-3 receptor 2, ... (6 entities in total)
• Functional Keywords: human relaxin family peptide receptor 4, g protein-coupled receptor, ligand recognition, structural protein
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 5
• Total formula weight: 154249.14

Authors

Chen, Y.,Zhou, Q.T.,Wang, J.,Xu, Y.W.,Wang, Y.,Yan, J.H.,Wang, Y.B.,Zhu, Q.,Zhao, F.H.,Li, C.H.,Chen, C.W.,Cai, X.Q.,Bathgate, R.A.D.,Shen, C.,Liu, H.,Xu, H.E.,Yang, D.H.,Wang, M.W. (deposition date: 2022-07-21, release date: 2023-03-01, Last modification date: 2024-10-30)

Primary citation

Chen, Y.,Zhou, Q.,Wang, J.,Xu, Y.,Wang, Y.,Yan, J.,Wang, Y.,Zhu, Q.,Zhao, F.,Li, C.,Chen, C.W.,Cai, X.,Bathgate, R.A.D.,Shen, C.,Eric Xu, H.,Yang, D.,Liu, H.,Wang, M.W.
Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4).
Nat Commun, 14:492-492, 2023

PubMed Abstract: Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4-G protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053. The B chain of INSL5 adopts a single α-helix that penetrates into the orthosteric pocket, while the A chain sits above the orthosteric pocket, revealing a peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. Our findings not only provide insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, but also expand the knowledge of signaling mechanisms in the insulin superfamily.

PubMed: 36717591
DOI: 10.1038/s41467-023-36182-z

Experimental method

ELECTRON MICROSCOPY (3.03 Å)