Cryo-EM structure of the human chemerin receptor 1–Gi protein complex bound to the C-terminal nonapeptide of chemerin

• DOI: 10.1073/pnas.2214324120
• Publication Date: 2023-03-07T18:45:15Z
• Authors: Junlin Wang; Geng Chen; Qiwen Liao; Wenping Lyu; Aijun Liu; Lizhe Zhu; Yang Du; Richard D. Ye
• Keywords: Chemerin

Chemerin is a processed protein that acts on G protein-coupled receptors (GPCRs) for its chemotactic and adipokine activities. The biologically active chemerin (chemerin 21-157) results from proteolytic cleavage of prochemerin uses C-terminal peptide containing the sequence YFPGQFAFS receptor activation. Here we report high-resolution cryo-electron microscopy (cryo-EM) structure human 1 (CMKLR1) bound to nonapeptide chemokine (C9) in complex with Gi proteins. C9 inserts C terminus into binding pocket stabilized through hydrophobic interactions involving Y1, F2, F6, F8, as well polar between G4, S9, several amino acids lining CMKLR1. Microsecond scale molecular dynamics simulations support balanced force distribution across whole ligand-receptor interface enhances thermodynamic stability captured pose C9. interaction CMKLR1 drastically different recognition by receptors, which follow two-site two-step model. In contrast, takes an "S"-shaped much like angiotensin II AT1 receptor. Our mutagenesis functional analyses confirmed cryo-EM key residues these interactions. findings provide structural basis established