Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy. / Miles, Timothy F.; Spiess, Katja; Jude, Kevin M.; Tsutsumi, Naotaka; Burg, John S.; Ingram, Jessica R.; Waghray, Deepa; Hjorto, Gertrud M.; Larsen, Olav; Ploegh, Hidde L.; Rosenkilde, Mette M.; Garcia, K. Christopher.
I: eLife, Bind 7, e35850 , 2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy
AU - Miles, Timothy F.
AU - Spiess, Katja
AU - Jude, Kevin M.
AU - Tsutsumi, Naotaka
AU - Burg, John S.
AU - Ingram, Jessica R.
AU - Waghray, Deepa
AU - Hjorto, Gertrud M.
AU - Larsen, Olav
AU - Ploegh, Hidde L.
AU - Rosenkilde, Mette M.
AU - Garcia, K. Christopher
PY - 2018
Y1 - 2018
N2 - Human 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
AB - Human 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
U2 - 10.7554/eLife.35850
DO - 10.7554/eLife.35850
M3 - Journal article
C2 - 29882741
VL - 7
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e35850
ER -
ID: 213286026