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Title: Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody

Abstract

The MERS-CoV is an emerging virus, which already infected more than 1,300 humans with high (~36%) mortality. Here, we show that m336, an exceptionally potent human anti-MERS-CoV antibody, is almost germline with only one somatic mutation in the heavy chain. The structure of Fab m336 in complex with the MERS-CoV receptor-binding domain reveals that its IGHV1-69-derived heavy chain provides more than 85% binding surface and that its epitope almost completely overlaps with the receptor-binding site. Analysis of antibodies from 69 healthy humans suggests an important role of the V(D)J recombination-generated junctional and allele-specific residues for achieving high affinity of binding at such low levels of somatic hypermutation. Our results also have important implications for development of vaccine immunogens based on the newly identified m336 epitope as well as for elucidation of mechanisms of neutralization by m336-like antibodies and their elicitation in vivo.

Authors:
 [1];  [2];  [3];  [4];  [2];  [2];  [4];  [5];  [6];  [2];  [4]
  1. Fudan Univ., Shanghai (China). Shanghai Medical College
  2. National Inst. of Health (NIH), Frederick, MD (United States). National Cancer Inst.
  3. New York Blood Center, New York, NY (United States). Lindsley F. Kimball Research Inst.
  4. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases
  5. Fudan Univ., Shanghai (China). Shanghai Medical College; National Inst. of Health (NIH), Frederick, MD (United States). National Cancer Inst.
  6. Fudan Univ., Shanghai (China). Shanghai Medical College; New York Blood Center, New York, NY (United States). Lindsley F. Kimball Research Inst.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1214653
Grant/Contract Number:  
W-31-109-ENG-38
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Ying, Tianlei, Prabakaran, Ponraj, Du, Lanying, Shi, Wei, Feng, Yang, Wang, Yanping, Wang, Lingshu, Li, Wei, Jiang, Shibo, Dimitrov, Dimiter S., and Zhou, Tongqing. Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody. United States: N. p., 2015. Web. doi:10.1038/ncomms9223.
Ying, Tianlei, Prabakaran, Ponraj, Du, Lanying, Shi, Wei, Feng, Yang, Wang, Yanping, Wang, Lingshu, Li, Wei, Jiang, Shibo, Dimitrov, Dimiter S., & Zhou, Tongqing. Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody. United States. doi:10.1038/ncomms9223.
Ying, Tianlei, Prabakaran, Ponraj, Du, Lanying, Shi, Wei, Feng, Yang, Wang, Yanping, Wang, Lingshu, Li, Wei, Jiang, Shibo, Dimitrov, Dimiter S., and Zhou, Tongqing. Tue . "Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody". United States. doi:10.1038/ncomms9223. https://www.osti.gov/servlets/purl/1214653.
@article{osti_1214653,
title = {Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody},
author = {Ying, Tianlei and Prabakaran, Ponraj and Du, Lanying and Shi, Wei and Feng, Yang and Wang, Yanping and Wang, Lingshu and Li, Wei and Jiang, Shibo and Dimitrov, Dimiter S. and Zhou, Tongqing},
abstractNote = {The MERS-CoV is an emerging virus, which already infected more than 1,300 humans with high (~36%) mortality. Here, we show that m336, an exceptionally potent human anti-MERS-CoV antibody, is almost germline with only one somatic mutation in the heavy chain. The structure of Fab m336 in complex with the MERS-CoV receptor-binding domain reveals that its IGHV1-69-derived heavy chain provides more than 85% binding surface and that its epitope almost completely overlaps with the receptor-binding site. Analysis of antibodies from 69 healthy humans suggests an important role of the V(D)J recombination-generated junctional and allele-specific residues for achieving high affinity of binding at such low levels of somatic hypermutation. Our results also have important implications for development of vaccine immunogens based on the newly identified m336 epitope as well as for elucidation of mechanisms of neutralization by m336-like antibodies and their elicitation in vivo.},
doi = {10.1038/ncomms9223},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {2015},
month = {9}
}

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