Stable Binding of Full‐Length Chemerin Is Driven by Negative Charges in the CMKLR1 N Terminus

Abstract

The adipokine chemerin is the endogenous ligand of the chemokine‐like receptor 1 (CMKLR1), a member of the family of G protein‐coupled receptors (GPCRs). This protein ligand plays an important role in obesity and inflammatory processes. Stable receptor–ligand interactions are highly relevant for its different physiological effects such as the migration of immune cells towards sites of inflammation. Here, we demonstrate that negative charges in the CMKLR1 N terminus are involved in the formation of strong contacts with a specific positively charged patch at the surface of full‐length chemerin, which is absent in the short nonapeptide agonist chemerin‐9, thus explaining its reduced affinity. Using receptor chimera of G protein‐coupled receptor 1 (GPR1) and CMKLR1, we were able to identify the residues of this interaction and its relevance for stable full‐length chemerin binding. This could help to develop more potent ligands for the treatment of inflammation‐related diseases.

Cryo-EM structures of the human G-protein coupled receptor 1 (GPR1) – Gi protein complexes bound to the full-length chemerin and to its C-terminal nonapeptide

“…At chemerin binding region 1 (CBR1), multiple polar and non-polar interactions between the N-terminus of GPR1 (CBR1) and the cavity formed between H1 helix and ý1 sheet of the N-terminal core of chemerin stabilize the chemerin binding. The importance of GPR1 N-terminal CBR1 in stable chemerin binding is reported recently using chimeric receptor-based binding assays (Kretschmer et al, 2023). At chemerin binding region 2 at the receptor TM pocket, contacts between the C-terminus of chemerin (C-terminal nonapeptides, structurally identical to C9 peptide) and CBR2 residues activate GPR1 downstream signaling.…”