Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor.
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.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
John S
JS
Burg
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Jessica R
JR
Ingram
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Computer Science, Stanford University, Stanford, CA 94305, USA. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
A J
AJ
Venkatakrishnan
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Kevin M
KM
Jude
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abhiram
A
Dukkipati
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Computer Science, Stanford University, Stanford, CA 94305, USA. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
Evan N
EN
Feinberg
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Alessandro
A
Angelini
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Deepa
D
Waghray
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Computer Science, Stanford University, Stanford, CA 94305, USA. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
Ron O
RO
Dror
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Hidde L
HL
Ploegh
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.
K Christopher
KC
Garcia
D065100:CCR5 Receptor Antagonists / Q000737:chemistry; D054428:Chemokine CX3CL1 / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry; D006801:Humans; D008024:Ligands; D000077592:Maraviroc; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D019707:Receptors, Chemokine / Q000819:agonists / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry; D014764:Viral Proteins / Q000819:agonists / Q000737:chemistry*
D065100:CCR5 Receptor Antagonists; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D003510:Cyclohexanes; D008024:Ligands; D010880:Piperidines; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D014230:Triazoles; C411191:US28 receptor, Cytomegalovirus; C473351:VUF 2274; D014764:Viral Proteins; D000077592:Maraviroc