8EK1

Cryo-EM structure of a potent anti-malarial antibody L9 in complex with Plasmodium falciparum circumsporozoite protein (PfCSP)(dominant class)

Summary for 8EK1

• Entry DOI: 10.2210/pdb8ek1/pdb
• EMDB information: 28192
• Descriptor: L9 Fab heavy chain, L9 Fab light chain, Circumsporozoite protein (3 entities in total)
• Functional Keywords: anti-malarial, pfcsp, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 182025.56

Authors

Tripathi, P.,Kwong, P.D. (deposition date: 2022-09-19, release date: 2023-03-15, Last modification date: 2025-05-14)

Primary citation

Tripathi, P.,Bender, M.F.,Lei, H.,Da Silva Pereira, L.,Shen, C.H.,Bonilla, B.,Dillon, M.,Ou, L.,Pancera, M.,Wang, L.T.,Zhang, B.,Batista, F.D.,Idris, A.H.,Seder, R.A.,Kwong, P.D.
Cryo-EM structures of anti-malarial antibody L9 with circumsporozoite protein reveal trimeric L9 association and complete 27-residue epitope.
Structure, 31:480-491.e4, 2023

PubMed Abstract: Monoclonal antibody L9 recognizes the Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective following controlled human malaria challenge. To gain insight into its function, we determined cryoelectron microscopy (cryo-EM) structures of L9 in complex with full-length PfCSP and assessed how this recognition influenced protection by wild-type and mutant L9s. Cryo-EM reconstructions at 3.6- and 3.7-Å resolution revealed L9 to recognize PfCSP as an atypical trimer. Each of the three L9s in the trimer directly recognized an Asn-Pro-Asn-Val (NPNV) tetrapeptide on PfCSP and interacted homotypically to facilitate L9-trimer assembly. We analyzed peptides containing different repeat tetrapeptides for binding to wild-type and mutant L9s to delineate epitope and homotypic components of L9 recognition; we found both components necessary for potent malaria protection. Last, we found the 27-residue stretch recognized by L9 to be highly conserved in P. falciparum isolates, suggesting the newly revealed complete L9 epitope to be an attractive vaccine target.

PubMed: 36931276
DOI: 10.1016/j.str.2023.02.009

Experimental method

ELECTRON MICROSCOPY (3.6 Å)