Research Article

Structural basis for chemokine recognition and activation of a viral G protein–coupled receptor

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Science  06 Mar 2015:
Vol. 347, Issue 6226, pp. 1113-1117
DOI: 10.1126/science.aaa5026

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Molecular “go” signals reveal their secrets

Chemokines are proteins that direct how cells move within the body. For instance, chemokines help immune cells locate invading pathogens and ensure that cells position themselves correctly within a developing organ. Cells detect chemokines through G protein–coupled receptors on their surface; however, the molecular details of how these proteins interact remain unclear (see the Perspective by Standfuss). Qin et al. solved the crystal structure of the chemokine receptor CXCR4 bound to the viral chemokine vMIP-II. Burg et al. solved the crystal structure of a viral chemokine receptor bound to the chemokine domain of CX3CL1. Given the role of chemokines in a number of diseases, these results may help in future drug design.

Science, this issue p. 1117, p. 1113; see also p. 1071

Abstract

Chemokines are small proteins that function as immune modulators through activation of chemokine G protein–coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state–like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor’s inactive state.

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