Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1

doi:10.1073/pnas.152147499

Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1

^*Center for Biophysical Sciences and Engineering, ^†Department of Microbiology, University of Alabama, 1025 18th Street South, Birmingham, AL 35294; and ^‡Center for Comparative Medicine, University of California, County Road 98 and Hutchison Drive, Davis, CA 95616

Edited by James A. Wells, Sunesis Pharmaceuticals, Inc., South San Francisco, CA, and approved May 23, 2002 (received for review March 12, 2002)

Abstract

Human IL-10 (hIL-10) modulates critical immune and inflammatory responses by way of interactions with its high- (IL-10R1) and low-affinity (IL-10R2) cell surface receptors. Human cytomegalovirus exploits the IL-10 signaling pathway by expressing a functional viral IL-10 homolog (cmvIL-10), which shares only 27% sequence identity with hIL-10 yet signals through IL-10R1 and IL-10R2. To define the molecular basis of this virus–host interaction, we determined the 2.7-Å crystal structure of cmvIL-10 bound to the extracellular fragment of IL-10R1 (sIL-10R1). The structure reveals cmvIL-10 forms a disulfide-linked homodimer that binds two sIL-10R1 molecules. Although cmvIL-10 and hIL-10 share similar intertwined topologies and sIL-10R1 binding sites, their respective interdomain angles differ by ∼40°. This difference results in a striking re-organization of the IL-10R1s in the putative cell surface complex. Solution binding studies show cmvIL-10 and hIL-10 share essentially identical affinities for sIL-10R1 whereas the Epstein–Barr virus IL-10 homolog (ebvIL-10), whose structure is highly similar to hIL-10, exhibits a ∼20-fold reduction in sIL-10R1 affinity. Our results suggest cmvIL-10 and ebvIL-10 have evolved different molecular mechanisms to engage the IL-10 receptors that ultimately enhance the respective ability of their virus to escape immune detection.

Footnotes

↵ § To whom reprint requests should be addressed. E-mail: walter{at}uab.edu.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: Atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID code 1LQS).
Abbreviations:

cmv,

human cytomegalovirus;

ebv,

Epstein–Barr virus;

hIL-10,

human IL-10;

s,

soluble