biostudies-literatureKleist ABNIAID NIH HHSNHLBI NIH HHSNCI NIH HHSNIGMS NIH HHS3603-3622.e27https://www.ebi.ac.uk/biostudies/studies/S-EPMC12435897biostudies-literatureUnknown188(13)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.CellEncoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network.PMC12435897F30 CA236182K99 CA240689R37 AI058072F30 HL134253T32 GM080202R35 GM137836F30 CA196040Slodkowicz GWedemeyer MJMcGrail DJTalbot LJYi SSDishman AFSluter MCrawford KSPeterson FCChevigne AKleist ABMalinverni DBabu MMSzpakowska MVolkman BFSahni NThomas MAfalseEncoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network.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.2025-01-01T00:00:00Z2025 Jun2026-06-03T03:00:15.937Z2026-04-23T03:13:28.88ZS-EPMC124358974027391210.1016/j.cell.2025.03.046