@article{4a09e25214a44c5d893547ca82b717c6,
title = "An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain",
abstract = "IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.",
keywords = "COVID-19, SARS-CoV-2, antibodies, receptor-binding domain, spike protein, x-ray crystallography",
author = "Wu, {Nicholas C.} and Meng Yuan and Hejun Liu and Lee, {Chang Chun D.} and Xueyong Zhu and Sandhya Bangaru and Torres, {Jonathan L.} and Caniels, {Tom G.} and Brouwer, {Philip J.M.} and {van Gils}, {Marit J.} and Sanders, {Rogier W.} and Ward, {Andrew B.} and Wilson, {Ian A.}",
note = "Funding Information: We thank Henry Tien for technical support with the crystallization robot, Jeanne Matteson and Yuanzi Hua for contribution to mammalian cell culture, Wenli Yu for contribution to insect cell culture, and Robyn Stanfield for assistance in data collection. We are grateful to the staff of Stanford Synchrotron Radiation Laboratory (SSRL) Beamline 12-1 for assistance. This work was supported by NIH grant R00 AI139445 (N.C.W.); Bill and Melinda Gates Foundation grants OPP1170236 (A.B.W., I.A.W.), OPP1111923 , OPP1132237 , and INV-002022 (R.W.S.); and NIH HIV Vaccine Research and Design (HIVRAD) grant P01 AI110657 (R.W.S., A.B.W., I.A.W.). M.J.v.G. is a recipient of an AMC Fellowship, and R.W.S is a recipient of a Vici grant from the Netherlands Organisation for Scientific Research (NWO). Use of the SSRL, SLAC National Accelerator Laboratory is supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under contract DE-AC02-76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH National Institute of General Medical Sciences (including grant P41GM103393 ). Funding Information: We thank Henry Tien for technical support with the crystallization robot, Jeanne Matteson and Yuanzi Hua for contribution to mammalian cell culture, Wenli Yu for contribution to insect cell culture, and Robyn Stanfield for assistance in data collection. We are grateful to the staff of Stanford Synchrotron Radiation Laboratory (SSRL) Beamline 12-1 for assistance. This work was supported by NIH grant R00 AI139445 (N.C.W.); Bill and Melinda Gates Foundation grants OPP1170236 (A.B.W. I.A.W.), OPP1111923, OPP1132237, and INV-002022 (R.W.S.); and NIH HIV Vaccine Research and Design (HIVRAD) grant P01 AI110657 (R.W.S. A.B.W. I.A.W.). M.J.v.G. is a recipient of an AMC Fellowship, and R.W.S is a recipient of a Vici grant from the Netherlands Organisation for Scientific Research (NWO). Use of the SSRL, SLAC National Accelerator Laboratory is supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH National Institute of General Medical Sciences (including grant P41GM103393). N.C.W. M.Y. H.L. and I.A.W. conceived and designed the study. N.C.W. M.Y. H.L. and C.-C.D.L. expressed and purified the proteins. T.G.C. P.J.M.B. M.J.v.G. and R.W.S. provided antibody clones and sequences. S.B. J.L.T. and A.B.W. provided the nsEM maps and performed fitting. N.C.W. M.Y. H.L. and X.Z. performed the crystallization and X-ray data collection and determined and refined the X-ray structures. N.C.W. M.Y. H.L. C.-C.D.L. X.Z. and I.A.W. analyzed the data. N.C.W. M.Y. H.L. and I.A.W. wrote the paper. All authors reviewed and/or edited the paper. Amsterdam UMC previously filed a patent application that included SARS-CoV-2 antibodies COVA2-04 and COVA2-39 (Brouwer et al. 2020). Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = oct,
day = "20",
doi = "10.1016/j.celrep.2020.108274",
language = "English (US)",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}