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|3ona, resolution 2.60Å ()|
|Gene:||crmD (Ectromelia virus)|
The SECRET domain in complex with CX3CL1
Pathogens have evolved sophisticated mechanisms to evade detection and destruction by the host immune system. Large DNA viruses encode homologues of chemokines and their receptors, as well as chemokine-binding proteins (CKBPs) to modulate the chemokine network in host response. The SECRET domain (smallpox virus-encoded chemokine receptor) represents a new family of viral CKBPs that binds a subset of chemokines from different classes to inhibit their activities, either independently or fused with viral tumor necrosis factor receptors (vTNFRs). Here we present the crystal structures of the SECRET domain of vTNFR CrmD encoded by ectromelia virus and its complex with chemokine CX3CL1. The SECRET domain adopts a beta-sandwich fold and utilizes its beta-sheet I surface to interact with CX3CL1, representing a new chemokine-binding manner of viral CKBPs. Structure-based mutagenesis and biochemical analysis identified important basic residues in the 40s loop of CX3CL1 for the interaction. Mutation of corresponding acidic residues in the SECRET domain also affected the binding for other chemokines, indicating that the SECRET domain binds different chemokines in a similar manner. We further showed that heparin inhibited the binding of CX3CL1 by the SECRET domain and the SECRET domain inhibited RAW264.7 cell migration induced by CX3CL1. These results together shed light on the structural basis for the SECRET domain to inhibit chemokine activities by interfering with both chemokine-GAG and chemokine-receptor interactions.
Structural basis of chemokine sequestration by CrmD, a poxvirus-encoded tumor necrosis factor receptor., Xue X, Lu Q, Wei H, Wang D, Chen D, He G, Huang L, Wang H, Wang X, PLoS Pathog. 2011 Jul;7(7):e1002162. Epub 2011 Jul 28. PMID:21829356
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.