%0 Journal Article %1 schermeng2025binding %A Schermeng, Tina %A Liessmann, Fabian %A Katharina Ambrosius, Carla %A Meiler, Jens %A Beck-Sickinger, Annette G. %D 2025 %J ChemBioChem %K CMKLR1 Chemerin Computational_Protein Receptor modeling xack yaff %N 1 %P e202400695 %R https://doi.org/10.1002/cbic.202400695 %T Binding Mode of Cyclic Chemerin-9 Peptide and ChemerinS157 Protein at CMKLR1 %U https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cbic.202400695 %V 26 %X Abstract The chemokine-like receptor 1 (CMKLR1) is activated by the adipokine and chemoattractant protein chemerin. Cryo-EM structures of chemerin-9-CMKLR1-Gi have been published, where chemerin-9 is the nonapeptide of the C terminus of chemerinS157. Chemerin-9 is as active as the full-length protein in Ca2+-release but shows differences in equilibrium read-outs. An equally potent cyclic chemerin-9 variant (cC9) was reported previously. Now, we have built a computational model of CMKLR1 to investigate the binding mode of cC9 and chemerinS157 in comparison to chemerin-9. Differences were investigated using CMKLR1 variants. Double-mutant cycle analysis identified CMKLR1-F2.53 as the relevant position for Phe8-binding of cC9. Energy contribution revealed slight differences in Phe8-binding to CMKLR1-F2.53 and space for larger residues. This was confirmed as the chemerin-9 variant with 1-naphthyl-L-alanine at position 8 showed a 4-fold increased potency of 2 nM (pEC50=8.6±0.15). While chemerin-9 and cC9 share their interactions at the CMKLR1, chemerinS157 tolerates most mutations of CMKLR1 in the deep binding site. The computational model of chemerinS157 suggests a β-sheet interaction between the N-terminal CMKLR1-segment I25VVL28 and the β-sheet D108KVLGRLVH116 of ChemS157, which was confirmed experimentally. Our data add to the knowledge by identifying the binding mode of chemerinS157 and cC9 at CMKLR1, facilitating the future structure-based drug design.

@article{schermeng2025binding, abstract = {Abstract The chemokine-like receptor 1 (CMKLR1) is activated by the adipokine and chemoattractant protein chemerin. Cryo-EM structures of chemerin-9-CMKLR1-Gi have been published, where chemerin-9 is the nonapeptide of the C terminus of chemerinS157. Chemerin-9 is as active as the full-length protein in Ca2+-release but shows differences in equilibrium read-outs. An equally potent cyclic chemerin-9 variant (cC9) was reported previously. Now, we have built a computational model of CMKLR1 to investigate the binding mode of cC9 and chemerinS157 in comparison to chemerin-9. Differences were investigated using CMKLR1 variants. Double-mutant cycle analysis identified CMKLR1-F2.53 as the relevant position for Phe8-binding of cC9. Energy contribution revealed slight differences in Phe8-binding to CMKLR1-F2.53 and space for larger residues. This was confirmed as the chemerin-9 variant with 1-naphthyl-L-alanine at position 8 showed a 4-fold increased potency of 2 nM (pEC50=8.6±0.15). While chemerin-9 and cC9 share their interactions at the CMKLR1, chemerinS157 tolerates most mutations of CMKLR1 in the deep binding site. The computational model of chemerinS157 suggests a β-sheet interaction between the N-terminal CMKLR1-segment I25VVL28 and the β-sheet D108KVLGRLVH116 of ChemS157, which was confirmed experimentally. Our data add to the knowledge by identifying the binding mode of chemerinS157 and cC9 at CMKLR1, facilitating the future structure-based drug design.}, added-at = {2025-06-18T14:33:05.000+0200}, author = {Schermeng, Tina and Liessmann, Fabian and Katharina Ambrosius, Carla and Meiler, Jens and Beck-Sickinger, Annette G.}, biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/2cd347a21edd0571b32e86bf4540dd030/scadsfct}, doi = {https://doi.org/10.1002/cbic.202400695}, eprint = {https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/cbic.202400695}, interhash = {69200588c8f8457614550d4a06cf773f}, intrahash = {cd347a21edd0571b32e86bf4540dd030}, journal = {ChemBioChem}, keywords = {CMKLR1 Chemerin Computational_Protein Receptor modeling xack yaff}, number = 1, pages = {e202400695}, timestamp = {2025-08-21T11:13:08.000+0200}, title = {Binding Mode of Cyclic Chemerin-9 Peptide and ChemerinS157 Protein at CMKLR1}, url = {https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cbic.202400695}, volume = 26, year = 2025 }