skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structural insights into chemokine CCL17 recognition by antibody M116

; ;
Publication Date:
Sponsoring Org.:
OSTI Identifier:
Grant/Contract Number:
Resource Type:
Journal Article: Published Article
Journal Name:
Biochemistry and Biophysics Reports
Additional Journal Information:
Journal Volume: 13; Journal Issue: C; Related Information: CHORUS Timestamp: 2017-12-09 06:21:39; Journal ID: ISSN 2405-5808
Country of Publication:

Citation Formats

Teplyakov, Alexey, Obmolova, Galina, and Gilliland, Gary L. Structural insights into chemokine CCL17 recognition by antibody M116. Netherlands: N. p., 2018. Web. doi:10.1016/j.bbrep.2017.11.005.
Teplyakov, Alexey, Obmolova, Galina, & Gilliland, Gary L. Structural insights into chemokine CCL17 recognition by antibody M116. Netherlands. doi:10.1016/j.bbrep.2017.11.005.
Teplyakov, Alexey, Obmolova, Galina, and Gilliland, Gary L. 2018. "Structural insights into chemokine CCL17 recognition by antibody M116". Netherlands. doi:10.1016/j.bbrep.2017.11.005.
title = {Structural insights into chemokine CCL17 recognition by antibody M116},
author = {Teplyakov, Alexey and Obmolova, Galina and Gilliland, Gary L.},
abstractNote = {},
doi = {10.1016/j.bbrep.2017.11.005},
journal = {Biochemistry and Biophysics Reports},
number = C,
volume = 13,
place = {Netherlands},
year = 2018,
month = 3

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.bbrep.2017.11.005

Save / Share:
  • Chemokines play important roles in the immune system, not only recruiting leukocytes to the site of infection and inflammation but also guiding cell homing and cell development. The soluble poxvirusencoded protein vCCI, a CC chemokine inhibitor, can bind to human CC chemokines tightly to impair the host immune defense. This protein has no known homologs in eukaryotes, and may represent a potent method to stop inflammation. Previously, our structure of the vCCI:MIP-1β complex indicated that vCCI uses negatively charged residues in β-sheet II to interact with positively charged residues in the MIP-1βN-terminus, 20’s region and 40’s loop. However, the interactionsmore » between vCCI and other CC chemokines have not yet been fully explored. Here, we used NMR and fluorescence anisotropy to study the interaction between vCCI and eotaxin-1 (CCL11), another CC chemokine that is an important factor in the asthma response. NMR results reveal that the binding pattern is very similar to the vCCI:MIP-1βcomplex, and suggest that electrostatic interactions provide a major contribution to binding. Fluorescence anisotropy results on variants of eotaxin-1 further confirm the critical roles of the charged residues in eotaxin. Compared to wild-type eotaxin, single, double, or triple mutations at these critical charged residues weaken the binding. One exception is the K47A mutation that exhibits increased affinity for vCCI, which can be explained structurally. In addition, the binding affinity between vCCI and other wild type CC chemokines, MCP-1, MIP-1β and RANTES, were determined as 1.09 nM, 1.16 nM, and 0.22 nM, respectively. To our knowledge, this is the first work quantitatively measuring the binding affinity between vCCI and different CC chemokines.« less
  • CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokinemore » interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.« less
  • 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 suggestmore » 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.« less