7RXP

Fab1512 in complex with the C-terminal alpha-TSR domain of P. falciparum

Summary for 7RXP

• Entry DOI: 10.2210/pdb7rxp/pdb
• Descriptor: Fab1512 light chain, Fab1512 heavy chain, Circumsporozoite protein, ... (4 entities in total)
• Functional Keywords: malaria, antibody, sporozoite, circumsporozoite protein, alpha-tsr domain, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 56498.35

Authors

Pholcharee, T.,Oyen, D.,Wilson, I.A. (deposition date: 2021-08-23, release date: 2022-03-16, Last modification date: 2024-10-30)

Primary citation

Beutler, N.,Pholcharee, T.,Oyen, D.,Flores-Garcia, Y.,MacGill, R.S.,Garcia, E.,Calla, J.,Parren, M.,Yang, L.,Volkmuth, W.,Locke, E.,Regules, J.A.,Dutta, S.,Emerling, D.,Early, A.M.,Neafsey, D.E.,Winzeler, E.,King, C.R.,Zavala, F.,Burton, D.R.,Wilson, I.A.,Rogers, T.F.
A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum.
Plos Pathog., 18:e1010409-e1010409, 2022

PubMed Abstract: Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved β-sheet face of the ctCSP (denoted β-ctCSP). Antibodies to the β-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of P. falciparum whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the β-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design.

PubMed: 35344575
DOI: 10.1371/journal.ppat.1010409

Experimental method

X-RAY DIFFRACTION (1.761 Å)