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Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody

Esswein, Shannon R. and Gristick, Harry B. and Jurado, Andrea and Peace, Avery and Keeffe, Jennifer R. and Lee, Yu E. and Voll, Alisa V. and Saeed, Mohsan and Nussenzweig, Michel C. and Rice, Charles M. and Robbiani, Davide F. and MacDonald, Margaret R. and Bjorkman, Pamela J. (2020) Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody. Proceedings of the National Academy of Sciences of the United States of America, 117 (18). pp. 9865-9875. ISSN 0027-8424. PMCID PMC7211955 .

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Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.

Item Type:Article
Related URLs:
URLURL TypeDescription Information CentralArticle
Esswein, Shannon R.0000-0002-5142-0190
Jurado, Andrea0000-0002-4023-8000
Peace, Avery0000-0003-3074-1662
Saeed, Mohsan0000-0001-8505-7054
Nussenzweig, Michel C.0000-0003-0592-8564
Rice, Charles M.0000-0003-3087-8079
Robbiani, Davide F.0000-0001-7379-3484
MacDonald, Margaret R.0000-0001-5177-2068
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2020 National Academy of Sciences. Published under the PNAS license. Edited by Stephen C. Harrison, Boston Children’s Hospital, Boston, MA, and approved March 23, 2020 (received for review November 3, 2019). PNAS first published April 22, 2020. We thank Dr. Jost Vielmetter at the Caltech Protein Expression Center funded by the Beckman Institute at the California Institute of Technology for protein expression and surface plasmon resonance instrument usage; Dr. Jens Kaiser at the California Institute of Technology Molecular Observatory for assistance with X-ray data collection; Dr. Anthony West for discussions regarding germline gene assignments; Alex Cohen for suggestions on EDIII production; Dr. Christopher Barnes for coordinating Advanced Photon Source (APS) beamline collection and beamline scientists at Stanford Synchrotron Radiation Lightsource and APS GM/CA 23-ID-D; and Dr. Ted Pierson for providing pDENV1/WP/CprME and pDENV2/16681/CprME plasmids. The California Institute of Technology Molecular Observatory is supported by the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program. Operations at Stanford Synchrotron Radiation Lightsource are supported by the US Department of Energy and NIH. Operations at APS are supported by US Department of Energy. This work was supported by NIH Grant P01AI138938 (to D.F.R., C.M.R., M.C.N., P.J.B.); NIH Training Grant 5-T32-GM007616-40 (to S.R.E.); NIH National Research Service Award Fellowship F30AI147579 (to S.R.E.); and NIH National Institute of General Medical Sciences Training Grant T32-GM008042 (to S.R.E.) through the University of California, Los Angeles–California Institute of Technology Medical Scientist Training Program. Data Availability: Crystallographic coordinates for structures Z004_(iGL) Fab–ZIKV EDIII and Z032_(mature) Fab–WNV EDIII are available from the Protein Data Bank under ID codes 6UTA and 6UTE. Author contributions: S.R.E., J.R.K., M.R.M., and P.J.B. designed research; S.R.E., H.B.G., A.J., A.P., Y.E.L., and A.V.V. performed research; S.R.E., Y.E.L., M.S., M.C.N., C.M.R., and D.F.R. contributed new reagents/analytic tools; S.R.E., J.R.K., D.F.R., M.R.M., and P.J.B. analyzed data; and S.R.E. and P.J.B. wrote the paper. Competing interest statement: D.F.R., M.C.N., and The Rockefeller University have filed a patent application for antibody Z004. This article is a PNAS Direct Submission. Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, (PDB ID codes 6UTA and 6UTE). This article contains supporting information online at
Funding AgencyGrant Number
Caltech Beckman InstituteUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Sanofi-Aventis Bioengineering Research ProgramUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
NIH Predoctoral Fellowship5-T32-GM007616-40
NIH Postdoctoral FellowshipF30AI147579
NIH Predoctoral FellowshipT32-GM008042
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
Subject Keywords:Zika; germline antibody; flavivirus; affinity maturation; antibody-dependent enhancement
Issue or Number:18
PubMed Central ID:PMC7211955
Record Number:CaltechAUTHORS:20200422-131710102
Persistent URL:
Official Citation:Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody. Shannon R. Esswein, Harry B. Gristick, Andrea Jurado, Avery Peace, Jennifer R. Keeffe, Yu E. Lee, Alisa V. Voll, Mohsan Saeed, Michel C. Nussenzweig, Charles M. Rice, Davide F. Robbiani, Margaret R. MacDonald, Pamela J. Bjorkman. Proceedings of the National Academy of Sciences May 2020, 117 (18) 9865-9875; DOI: 10.1073/pnas.1919269117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102721
Deposited By: Tony Diaz
Deposited On:22 Apr 2020 21:10
Last Modified:02 Jun 2020 18:31

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