@article{b957ca36dbf240f3b6a446ccf515e15e,
title = "Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network",
abstract = "In humans, selective and promiscuous interactions between 46 secreted chemokine ligands and 23 cell surface chemokine receptors of the G-protein-coupled receptor (GPCR) family form a complex network to coordinate cell migration. While chemokines and their GPCRs each share common structural scaffolds, the molecular principles driving selectivity and promiscuity remain elusive. Here, we identify conserved, semi-conserved, and variable determinants (i.e., recognition elements) that are encoded and decoded by chemokines and their receptors to mediate interactions. Selectivity and promiscuity emerge from an ensemble of generalized (“public/conserved”) and specific (“private/variable”) determinants distributed among structured and unstructured protein regions, with ligands and receptors recognizing these determinants combinatorially. We employ these principles to engineer a viral chemokine with altered GPCR coupling preferences and provide a web resource to facilitate sequence-structure-function studies and protein design efforts for developing immuno-therapeutics and cell therapies.",
keywords = "chemokine, chemotaxis, data science, GPCR, machine learning, polymorphism, protein-protein interaction, selectivity determinants, short linear motif, unstructured protein, Amino Acid Sequence, Humans, Models, Molecular, Chemokines/metabolism, Receptors, Chemokine/metabolism, Receptors, G-Protein-Coupled/metabolism, Protein Binding, Ligands",
author = "Kleist, \{Andrew B.\} and Martyna Szpakowska and Talbot, \{Lindsay J.\} and Greg Slodkowicz and Duccio Malinverni and Thomas, \{Monica A.\} and Crawford, \{Kyler S.\} and McGrail, \{Daniel J.\} and Dishman, \{Acacia F.\} and Wedemeyer, \{Michael J.\} and Madison Sluter and Yi, \{S. Stephen\} and Nidhi Sahni and Peterson, \{Francis C.\} and Andy Chevign{\'e} and Volkman, \{Brian F.\} and Babu, \{M. Madan\}",
note = "Funding: This work was supported by American Lebanese Syrian Associated Charities (to M.M.B., D.M., M. Sluter, and L.J.T.); Medical Research Council grants MC\_U105185859 (to M.M.B., D.M., and G.S.); The Lister Institute for Preven- tative Medicine (to M.M.B. and A.B.K.); NIH grants F30CA196040 (to A.B.K.), R37AI058072 (to B.F.V.), F30HL134253 (to M.A.T.), F30CA236182 (to A.F.D.), T32GM080202 (to A.B.K., M.A.T., K.S.C., and A.F.D.), R35GM137836 (to N.S.), K99CA240689 (to D.J.M.); Luxembourg Institute of Health NanoLux Platform (to M. Szpakowska and A.C.); Luxembourg National Research Fund INTER/FNRS grants INTER 20/15084569 and CORE C23/BM/ 18068832 (to M. Szpakowska and A.C.); F.R.S.-FNRS-Te´ le´ vie grants 7.8504.20, 7.4502.21, and 7.8508.22 (M. Szpakowska and A.C.); St. Jude GPCR Research Collaborative (to M.M.B.); AstraZeneca Blue Sky Fund grant BSF17 (to M.M.B. and G.S.); Swiss National Science Foundation grant P2ELP3\_18910 (to D.M.); CPRIT Scholar in Cancer Research grant RR160021 (to N.S.); Alfred P. Sloan Scholar Research Fellowship grant FG- 2018-10723 (to N.S.); Blanton-Davis Ovarian Cancer Research Program (to N.S.); Andrew Sabin Family Foundation Fellowship (to N.S.); Ovarian Cancer Research Alliance Early Career Award grant 649968 (to N.S.). Publisher Copyright: {\textcopyright} 2025 The Authors",
year = "2025",
month = jun,
day = "26",
doi = "10.1016/j.cell.2025.03.046",
language = "English",
volume = "188",
pages = "3603--3622.e27",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "13",
}