8EH5

Cryo-EM structure of L9 Fab in complex with rsCSP

Summary for 8EH5

• Entry DOI: 10.2210/pdb8eh5/pdb
• EMDB information: 28135
• Descriptor: Circumsporozoite protein, L9 Heavy chain, L9 Light chain (3 entities in total)
• Functional Keywords: pfcsp, malaria, antibody, immune system
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum); More
• Total number of polymer chains: 7
• Total formula weight: 174581.42

Authors

Martin, G.M.,Ward, A.B. (deposition date: 2022-09-13, release date: 2023-06-28, Last modification date: 2024-11-13)

Primary citation

Martin, G.M.,Fernandez-Quintero, M.L.,Lee, W.H.,Pholcharee, T.,Eshun-Wilson, L.,Liedl, K.R.,Pancera, M.,Seder, R.A.,Wilson, I.A.,Ward, A.B.
Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9.
Nat Commun, 14:2815-2815, 2023

PubMed 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.

PubMed: 37198165
DOI: 10.1038/s41467-023-38509-2

Experimental method

ELECTRON MICROSCOPY (3.36 Å)