The Chemokine Receptor, US28
Figure: Surface representation of the
chemokine ligand, CX3CL1 (blue), bound to the viral chemokine GPCR US28
Chris Garcia group (Stanford University)
Given the importance of chemokines in various pathologies
and in drug development, Chris Garcia's group at Stanford University solved
the structure of a different GPCR:protein complex -- an activated
cytomegalovirus GPCR, US28, bound to its human chemokine ligand, CX3CL1. In
this case, US28 is a viral GPCR that binds a human chemokine to subvert the
host immune system. The structure revealed how the N-terminus of the
chemokine enters the binding pocket of the receptor in the center of the
7-helix bundle. The N-terminus of the receptor binds to a conserved groove on
the surface of the chemokine. The structure also revealed a unique amino acid
network that destabilizes the receptor's inactive state, contributing to its
constitutive activity. These findings offer insights into GPCR ligand binding
and receptor activation that advance the understanding of mechanisms of
immune evasion and will guide rational drug design.
Citation: John S. Burg, Jessica R. Ingram, A.J.
Venkatakrishnan, Kevin M. Jude, Abhiram Dukkipati, Evan N. Feinberg,
Alessandro Angelini, Deepa Waghray, Ron O. Dror, Hidde L. Ploegh, K.
Christopher Garcia, "Structural basis for chemokine recognition and
activation of a viral G protein–coupled receptor," Science 347,
1113-1117 (2015). DOI: 10.1126/science.aaa5026