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Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9

Author

Listed:
  • Gregory M. Martin

    (The Scripps Research Institute)

  • Monica L. Fernández-Quintero

    (The University of Innsbruck; Innrain 80-82/III)

  • Wen-Hsin Lee

    (The Scripps Research Institute)

  • Tossapol Pholcharee

    (The Scripps Research Institute
    University of Oxford)

  • Lisa Eshun-Wilson

    (The Scripps Research Institute)

  • Klaus R. Liedl

    (The University of Innsbruck; Innrain 80-82/III)

  • Marie Pancera

    (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center)

  • Robert A. Seder

    (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Ian A. Wilson

    (The Scripps Research Institute
    The Skaggs Institute for Chemical Biology, The Scripps Research Institute)

  • Andrew B. Ward

    (The Scripps Research Institute)

Abstract

A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure of the highly potent anti-PfCSP antibody L9 in complex with recombinant PfCSP. We found that L9 Fab binds multivalently to the minor (NPNV) repeat domain, which is stabilized by a unique set of affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed a critical role of the L9 light chain in integrity of the homotypic interface, which likely impacts PfCSP affinity and protective efficacy. These findings reveal the molecular mechanism of the unique NPNV selectivity of L9 and emphasize the importance of anti-homotypic affinity maturation in protective immunity against P. falciparum.

Suggested Citation

  • Gregory M. Martin & Monica L. Fernández-Quintero & Wen-Hsin Lee & Tossapol Pholcharee & Lisa Eshun-Wilson & Klaus R. Liedl & Marie Pancera & Robert A. Seder & Ian A. Wilson & Andrew B. Ward, 2023. "Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38509-2
    DOI: 10.1038/s41467-023-38509-2
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    References listed on IDEAS

    as
    1. Susanna Röblitz & Marcus Weber, 2013. "Fuzzy spectral clustering by PCCA+: application to Markov state models and data classification," Advances in Data Analysis and Classification, Springer;German Classification Society - Gesellschaft für Klassifikation (GfKl);Japanese Classification Society (JCS);Classification and Data Analysis Group of the Italian Statistical Society (CLADAG);International Federation of Classification Societies (IFCS), vol. 7(2), pages 147-179, June.
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