5wb2
From Proteopedia
US28 bound to engineered chemokine CX3CL1.35 and nanobodies
Structural highlights
FunctionUS28_HCMVT Receptor for a C-C type chemokine. Binds to a great number of different CC-chemokines including CCL5/RANTES, CCL2/MCP-1, CCL3/MIP-1-alpha as well as CX3CL1/Fractalkine (PubMed:29882741). Transduces signals resulting in the activation of MAP kinase signaling pathways and augmentation of intracellular calcium ion levels, leading to alterations in chemotactic behavior of vascular smooth muscle cells and macrophages. The US28 receptor also exhibits high levels of agonist-independent signaling activity and agonist-independent endocytosis. Interacts with the host Gi complex without activating it, thereby probably interfering with the chemokine-Gi signaling. May also function as a G protein sink to sequester G protein from the cell surface via internalization. Interacts with endogenous Gaq/11 subunits and thereby constitutively activates phospholipase C (By similarity).[UniProtKB:P69332][1] Publication Abstract from PubMedHuman cytomegalovirus has hijacked and evolved a human G-protein-coupled receptor into US28, which functions as a promiscuous chemokine 'sink' to facilitate evasion of host immune responses. To probe the molecular basis of US28's unique ligand cross-reactivity, we deep-sequenced CX3CL1 chemokine libraries selected on 'molecular casts' of the US28 active-state and find that US28 can engage thousands of distinct chemokine sequences, many of which elicit diverse signaling outcomes. The structure of a G-protein-biased CX3CL1-variant in complex with US28 revealed an entirely unique chemokine amino terminal peptide conformation and remodeled constellation of receptor-ligand interactions. Receptor signaling, however, is remarkably robust to mutational disruption of these interactions. Thus, US28 accommodates and functionally discriminates amongst highly degenerate chemokine sequences by sensing the steric bulk of the ligands, which distort both receptor extracellular loops and the walls of the ligand binding pocket to varying degrees, rather than requiring sequence-specific bonding chemistries for recognition and signaling. Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy.,Miles TF, Spiess K, Jude KM, Tsutsumi N, Burg JS, Ingram JR, Waghray D, Hjorto GM, Larsen O, Ploegh HL, Rosenkilde MM, Garcia KC Elife. 2018 Jun 8;7. pii: 35850. doi: 10.7554/eLife.35850. PMID:29882741[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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