8FG0

Crystal structure of the 3764 Fab in complex with the C-terminal PfCSP linker, PfCSP281-294.

Summary for 8FG0

• Entry DOI: 10.2210/pdb8fg0/pdb
• Descriptor: 3764 Fab Heavy chain, 3764 Fab Light chain, Circumsporozoite protein, ... (4 entities in total)
• Functional Keywords: malaria, antibody, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 99214.54

Authors

Burn Aschner, C.,Julien, J.P. (deposition date: 2022-12-11, release date: 2023-05-10, Last modification date: 2024-10-30)

Primary citation

Oludada, O.E.,Costa, G.,Burn Aschner, C.,Obraztsova, A.S.,Prieto, K.,Canetta, C.,Hoffman, S.L.,Kremsner, P.G.,Mordmuller, B.,Murugan, R.,Julien, J.P.,Levashina, E.A.,Wardemann, H.
Molecular and functional properties of human Plasmodium falciparum CSP C-terminus antibodies.
Embo Mol Med, 15:e17454-e17454, 2023

PubMed Abstract: Human monoclonal antibodies (mAbs) against the central repeat and junction domain of Plasmodium falciparum circumsporozoite protein (PfCSP) have been studied extensively to guide malaria vaccine design compared to antibodies against the PfCSP C terminus. Here, we describe the molecular characteristics and protective potential of 73 germline and mutated human mAbs against the highly immunogenic PfCSP C-terminal domain. Two mAbs recognized linear epitopes in the C-terminal linker with sequence similarity to repeat and junction motifs, whereas all others targeted conformational epitopes in the α-thrombospondin repeat (α-TSR) domain. Specificity for the polymorphic Th2R/Th3R but not the conserved RII+/CS.T3 region in the α-TSR was associated with IGHV3-21/IGVL3-21 or IGLV3-1 gene usage. Although the C terminus specific mAbs showed signs of more efficient affinity maturation and class-switching compared to anti-repeat mAbs, live sporozoite binding and inhibitory activity was limited to a single C-linker reactive mAb with cross-reactivity to the central repeat and junction. The data provide novel insights in the human anti-C-linker and anti-α-TSR antibody response that support exclusion of the PfCSP C terminus from malaria vaccine designs.

PubMed: 37082831
DOI: 10.15252/emmm.202317454

Experimental method

X-RAY DIFFRACTION (2.36 Å)