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

Nat Commun. 2023-05; 
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
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Codon Optimization … L9 heavy and light chain sequences were synthesized and codon-optimized for mammalian expression and cloned into pHCMV3 by Genscript Inc. The full variable domain (V H /V L ) … Get A Quote

摘要

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 molecul... More

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