7V05

Complex of Plasmodium falciparum circumsporozoite protein with 850 Fab

Summary for 7V05

• Entry DOI: 10.2210/pdb7v05/pdb
• Related: 7UYL 7UYM
• EMDB information: 26936
• Descriptor: 850 Fab Heavy Chain, 850 Fab Light Chain, Circumsporozoite protein (3 entities in total)
• Functional Keywords: antibody, malaria, plasmodium falciparum, circumsporozoite protein, antimicrobial protein, immune system-cell invasion complex, immune system/cell invasion
• Biological source: Mus musculus; More
• Total number of polymer chains: 29
• Total formula weight: 707927.16

Authors

Kucharska, I.,Prieto, K.,Rubinstein, J.L.,Julien, J.P. (deposition date: 2022-05-09, release date: 2022-11-23, Last modification date: 2024-11-13)

Primary citation

Kucharska, I.,Binter, S.,Murugan, R.,Scally, S.W.,Ludwig, J.,Prieto, K.,Thai, E.,Costa, G.,Li, K.,Horn, G.Q.,Flores-Garcia, Y.,Bosch, A.,Sicard, T.,Rubinstein, J.L.,Zavala, F.,Dennison, S.M.,Tomaras, G.D.,Levashina, E.A.,Kellam, P.,Wardemann, H.,Julien, J.P.
High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire.
Plos Pathog., 18:e1010999-e1010999, 2022

PubMed Abstract: Antibodies targeting the human malaria parasite Plasmodium falciparum circumsporozoite protein (PfCSP) can prevent infection and disease. PfCSP contains multiple central repeating NANP motifs; some of the most potent anti-infective antibodies against malaria bind to these repeats. Multiple antibodies can bind the repeating epitopes concurrently by engaging into homotypic Fab-Fab interactions, which results in the ordering of the otherwise largely disordered central repeat into a spiral. Here, we characterize IGHV3-33/IGKV1-5-encoded monoclonal antibody (mAb) 850 elicited by immunization of transgenic mice with human immunoglobulin loci. mAb 850 binds repeating NANP motifs with picomolar affinity, potently inhibits Plasmodium falciparum (Pf) in vitro and, when passively administered in a mouse challenge model, reduces liver burden to a similar extent as some of the most potent anti-PfCSP mAbs yet described. Like other IGHV3-33/IGKV1-5-encoded anti-NANP antibodies, mAb 850 primarily utilizes its HCDR3 and germline-encoded aromatic residues to recognize its core NANP motif. Biophysical and cryo-electron microscopy analyses reveal that up to 19 copies of Fab 850 can bind the PfCSP repeat simultaneously, and extensive homotypic interactions are observed between densely-packed PfCSP-bound Fabs to indirectly improve affinity to the antigen. Together, our study expands on the molecular understanding of repeat-induced homotypic interactions in the B cell response against PfCSP for potently protective mAbs against Pf infection.

PubMed: 36441829
DOI: 10.1371/journal.ppat.1010999

Experimental method

ELECTRON MICROSCOPY (3.4 Å)