8zjg

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Cryo-EM structure of human CMKLR1-Gi complex bound to chemerin

Structural highlights

8zjg is a 6 chain structure with sequence from Homo sapiens and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.18Å
Ligands:CLR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CML1_HUMAN Receptor for the chemoattractant adipokine chemerin/RARRES2 and for the omega-3 fatty acid derived molecule resolvin E1. Interaction with RARRES2 initiates activation of G proteins G(i)/G(o) and beta-arrestin pathways inducing cellular responses via second messenger pathways such as intracellular calcium mobilization, phosphorylation of MAP kinases MAPK1/MAPK3 (ERK1/2), TYRO3, MAPK14/P38MAPK and PI3K leading to multifunctional effects, like reduction of immune responses, enhancing of adipogenesis and angionesis (PubMed:27716822). Resolvin E1 down-regulates cytokine production in macrophages by reducing the activation of MAPK1/3 (ERK1/2) and NF-kappa-B. Positively regulates adipogenesis and adipocyte metabolism.[1] [2] [3] [4] (Microbial infection) Acts as a coreceptor for several SIV strains (SIVMAC316, SIVMAC239, SIVMACL7E-FR and SIVSM62A), as well as a primary HIV-1 strain (92UG024-2).[5]

Publication Abstract from PubMed

Chemerin, a chemotactic adipokine, plays essential roles in adipogenesis and inflammation. Serum chemerin concentration is closely associated with obesity and metabolism disorders. The mature form of chemerin (residues 21-157) acts primarily through chemerin receptor 1 (CMKLR1) for transmembrane signaling. As a result, CMKLR1 serves as a promising target for therapeutic intervention of immunometabolic diseases such as diabetes and multiple sclerosis. Here, we present a high-resolution cryo-EM structure of CMKLR1-Gi signaling complex bound to biologically active full-length chemerin. The mature chemerin shows binding features distinct from its C-terminal nonapeptide including interaction with both the extracellular loops (ECLs) and the N-terminus of CMKLR1. Combining results from functional assays, our studies demonstrate that chemerin interacts with CMKLR1 in a "two-site" mode similar to chemokine-chemokine receptor interactions, but acting as a "reverse chemokine" by inserting its C-terminus instead of the N-terminus as in the case of chemokines into the transmembrane binding pocket of CMKLR1. These structural insights are expected to help develop synthetic analogs with therapeutic potential.

Structural basis for full-length chemerin recognition and signaling through chemerin receptor 1.,Liu A, Liu Y, Wang J, Ye RD Commun Biol. 2024 Nov 30;7(1):1598. doi: 10.1038/s42003-024-07228-9. PMID:39616240[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Vermi W, Riboldi E, Wittamer V, Gentili F, Luini W, Marrelli S, Vecchi A, Franssen JD, Communi D, Massardi L, Sironi M, Mantovani A, Parmentier M, Facchetti F, Sozzani S. Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J Exp Med. 2005 Feb 21;201(4):509-15. PMID:15728234 doi:10.1084/jem.20041310
  2. ↑ Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005 Mar 7;201(5):713-22. PMID:15753205 doi:10.1084/jem.20042031
  3. ↑ Kaur J, Adya R, Tan BK, Chen J, Randeva HS. Identification of chemerin receptor (ChemR23) in human endothelial cells: chemerin-induced endothelial angiogenesis. Biochem Biophys Res Commun. 2010 Jan 22;391(4):1762-8. PMID:20044979 doi:10.1016/j.bbrc.2009.12.150
  4. ↑ De Henau O, Degroot GN, Imbault V, Robert V, De Poorter C, Mcheik S, Galés C, Parmentier M, Springael JY. Signaling Properties of Chemerin Receptors CMKLR1, GPR1 and CCRL2. PLoS One. 2016 Oct 7;11(10):e0164179. PMID:27716822 doi:10.1371/journal.pone.0164179
  5. ↑ Samson M, Edinger AL, Stordeur P, Rucker J, Verhasselt V, Sharron M, Govaerts C, Mollereau C, Vassart G, Doms RW, Parmentier M. ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. Eur J Immunol. 1998 May;28(5):1689-700. PMID:9603476 doi:<1689::AID-IMMU1689>3.0.CO;2-I 10.1002/(SICI)1521-4141(199805)28:05<1689::AID-IMMU1689>3.0.CO;2-I
  6. ↑ Liu A, Liu Y, Wang J, Ye RD. Structural basis for full-length chemerin recognition and signaling through chemerin receptor 1. Commun Biol. 2024 Nov 30;7(1):1598. PMID:39616240 doi:10.1038/s42003-024-07228-9

Contents


PDB ID 8zjg

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