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Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies.

<div class='caption-title'>(A) Jurkat cell surface-displayed EBOV GP binding was assessed using fluorescently labeled EBOV-515 or EBOV-520 after prior incubation of cells with individual unlabeled glycan cap antibodies. The blue dotted line represents basal binding of base antibodies without glycan cap antibodies. The orange dotted line represents maximal binding of base antibodies to GPCL. Data are shown as mean ± SD of technical triplicates.</div>
<div class='caption-title'>(A) Low-pass-filtered glycan cap Fabs from cryo-EM structures solved in this study as well as elsewhere, bound to EBOV GPΔMuc, are overlaid to compare binding epitope and angle of approach.</div>
<div class='caption-title'>Single protomers from structural models are shown with close-up views of interacting regions. HCs are rendered in darker colors and LCs in lighter colors, with GP1 colored white. Important residues that coordinate interaction and binding are highlighted.</div>
Murin CD, Gilchuk P, Ilinykh PA, Huang K, Kuzmina N, Shen X, Bruhn JF, Bryan AL, Davidson E, Doranz BJ, Williamson LE, Copps J, Alkutkar T, Flyak AI, Bukreyev A, Crowe JE, Ward AB
OpenAccess logo Cell Rep 35 108984 (2021)
Related entries: 7kej, 7kew, 7kf9, 7kfb, 7kfe, 7kfg, 7kfh

Cited: 14 times
EuropePMC logo PMID: 33852862

Abstract

Antibodies that target the glycan cap epitope on the ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization are not well understood. Here, we present cryoelectron microscopy (cryo-EM) structures of diverse glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLDs) to the glycan cap, which we call the MLD anchor and cradle. Antibodies that bind to the MLD cradle share common features, including use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form β-hairpin structures to mimic the MLD anchor, disrupt MLD attachment, destabilize GP quaternary structure, and block cleavage events required for receptor binding. Our results provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies.

Articles - 7kex mentioned but not cited (2)

  1. Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies. Murin CD, Gilchuk P, Ilinykh PA, Huang K, Kuzmina N, Shen X, Bruhn JF, Bryan AL, Davidson E, Doranz BJ, Williamson LE, Copps J, Alkutkar T, Flyak AI, Bukreyev A, Crowe JE, Ward AB. Cell Rep 35 108984 (2021)
  2. Glycan shield of the ebolavirus envelope glycoprotein GP. Peng W, Rayaprolu V, Parvate AD, Pronker MF, Hui S, Parekh D, Shaffer K, Yu X, Saphire EO, Snijder J. Commun Biol 5 785 (2022)


Reviews citing this publication (4)

  1. Filovirus Neutralising Antibodies: Mechanisms of Action and Therapeutic Application. Hargreaves A, Brady C, Mellors J, Tipton T, Carroll MW, Longet S. Pathogens 10 1201 (2021)
  2. Development and Structural Analysis of Antibody Therapeutics for Filoviruses. Yu X, Saphire EO. Pathogens 11 374 (2022)
  3. Immune correlates of protection for SARS-CoV-2, Ebola and Nipah virus infection. Escudero-Pérez B, Lawrence P, Castillo-Olivares J. Front Immunol 14 1156758 (2023)
  4. Structural Biology Illuminates Molecular Determinants of Broad Ebolavirus Neutralization by Human Antibodies for Pan-Ebolavirus Therapeutic Development. Murin CD, Gilchuk P, Crowe JE, Ward AB. Front Immunol 12 808047 (2021)

Articles citing this publication (8)

  1. Pan-ebolavirus protective therapy by two multifunctional human antibodies. Gilchuk P, Murin CD, Cross RW, Ilinykh PA, Huang K, Kuzmina N, Borisevich V, Agans KN, Geisbert JB, Zost SJ, Nargi RS, Sutton RE, Suryadevara N, Bombardi RG, Carnahan RH, Bukreyev A, Geisbert TW, Ward AB, Crowe JE. Cell 184 5593-5607.e18 (2021)
  2. Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies. Engdahl TB, Binshtein E, Brocato RL, Kuzmina NA, Principe LM, Kwilas SA, Kim RK, Chapman NS, Porter MS, Guardado-Calvo P, Rey FA, Handal LS, Diaz SM, Zagol-Ikapitte IA, Tran MH, McDonald WH, Meiler J, Reidy JX, Trivette A, Bukreyev A, Hooper JW, Crowe JE. Elife 12 e81743 (2023)
  3. Ebola Virus Glycoprotein Domains Associated with Protective Efficacy. Bhatia B, Furuyama W, Hoenen T, Feldmann H, Marzi A. Vaccines (Basel) 9 630 (2021)
  4. Blocking of ebolavirus spread through intercellular connections by an MPER-specific antibody depends on BST2/tetherin. Santos RI, Ilinykh PA, Pietzsch CA, Ronk AJ, Huang K, Kuzmina NA, Zhou F, Crowe JE, Bukreyev A. Cell Rep 42 113254 (2023)
  5. Computational epitope mapping of class I fusion proteins using low complexity supervised learning methods. Fischer MFS, Crowe JE, Meiler J. PLoS Comput Biol 18 e1010230 (2022)
  6. Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region. Schoeder CT, Gilchuk P, Sangha AK, Ledwitch KV, Malherbe DC, Zhang X, Binshtein E, Williamson LE, Martina CE, Dong J, Armstrong E, Sutton R, Nargi R, Rodriguez J, Kuzmina N, Fiala B, King NP, Bukreyev A, Crowe JE, Meiler J. PLoS Pathog 18 e1010518 (2022)
  7. Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma. Gilchuk P, Guthals A, Bonissone SR, Shaw JB, Ilinykh PA, Huang K, Bombardi RG, Liang J, Grinyo A, Davidson E, Chen EC, Gunn BM, Alter G, Saphire EO, Doranz BJ, Bukreyev A, Zeitlin L, Castellana N, Crowe JE. Front Immunol 12 706757 (2021)
  8. Systematic analysis of human antibody response to ebolavirus glycoprotein shows high prevalence of neutralizing public clonotypes. Chen EC, Gilchuk P, Zost SJ, Ilinykh PA, Binshtein E, Huang K, Myers L, Bonissone S, Day S, Kona CR, Trivette A, Reidy JX, Sutton RE, Gainza C, Diaz S, Williams JK, Selverian CN, Davidson E, Saphire EO, Doranz BJ, Castellana N, Bukreyev A, Carnahan RH, Crowe JE. Cell Rep 42 112370 (2023)


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