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An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

Flyak, Andrew I. and Ruiz, Stormy E. and Salas, Jordan and Rho, Semi and Bailey, Justin R. and Bjorkman, Pamela J. (2020) An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein. eLife, 9 . Art. No. e53169. ISSN 2050-084X. PMCID PMC7064334. doi:10.7554/elife.53169.

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A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Flyak, Andrew I.0000-0002-8722-479X
Ruiz, Stormy E.0000-0003-0892-9626
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2020 Flyak et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 30 October 2019; Accepted: 02 March 2020; Published: 03 March 2020. We thank the Caltech Protein Expression Center (Dr. Jost Vielmetter, director) for help with protein expression and Dr. Anthony West for helpful discussions. Structural studies were assisted by the Caltech Molecular Observatory (Dr. Jens Kaiser, director). This research was supported by the National Institutes of Health grant R01 AI127469 (to JRB and PJB) (content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH) and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. AIF was a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by NIHGMS P41GM103393. Author contributions: Andrew I Flyak, Conceptualization, Data curation, Software, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing; Stormy E Ruiz, Formal analysis, Investigation, Writing - review and editing; Jordan Salas, Semi Rho, Data curation, Formal analysis, Investigation, Writing - review and editing; Justin R Bailey, Supervision, Funding acquisition, Investigation, Writing - review and editing; Pamela J Bjorkman, Conceptualization, Supervision, Funding acquisition, Project administration, Writing - review and editing. Competing interests: Pamela J Bjorkman: Reviewing editor, eLife. Andrew I Flyak, Justin R Bailey: AIF and JRB are inventors of International Patent Application, Serial no. PCT/US2019/029315, pertaining to some of the antibodies presented in this article. The other authors declare that no competing interests exist. Data availability: Diffraction data have been deposited in PDB under the accession code 6URH.
Funding AgencyGrant Number
NIHR01 AI127469
Gordon and Betty Moore FoundationUNSPECIFIED
Cancer Research InstituteUNSPECIFIED
Department of Energy (DOE)DE-AC02-76SF00515
PubMed Central ID:PMC7064334
Record Number:CaltechAUTHORS:20200312-143121974
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Official Citation:An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein. Flyak et al. eLife 2020;9:e53169; doi: 10.7554/elife.53169
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101899
Deposited By: Tony Diaz
Deposited On:12 Mar 2020 21:54
Last Modified:16 Nov 2021 18:06

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