8F9S

Crystal structure of Ky15.2 Fab in complex with circumsporozoite protein NDN peptide

Summary for 8F9S

• Entry DOI: 10.2210/pdb8f9s/pdb
• Descriptor: Ky15.2 Antibody, heavy chain, Ky15.2 Antibody, light chain, Circumsporozoite protein NDN peptide, ... (5 entities in total)
• Functional Keywords: malaria, antibody, immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 6
• Total formula weight: 98225.60

Authors

Thai, E.,Julien, J.P. (deposition date: 2022-11-24, release date: 2023-11-01, Last modification date: 2024-11-13)

Primary citation

Thai, E.,Murugan, R.,Binter, S.,Burn Aschner, C.,Prieto, K.,Kassardjian, A.,Obraztsova, A.S.,Kang, R.W.,Flores-Garcia, Y.,Mathis-Torres, S.,Li, K.,Horn, G.Q.,Huntwork, R.H.C.,Bolscher, J.M.,de Bruijni, M.H.C.,Sauerwein, R.,Dennison, S.M.,Tomaras, G.D.,Zavala, F.,Kellam, P.,Wardemann, H.,Julien, J.P.
Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein.
Cell Rep, 42:113330-113330, 2023

PubMed Abstract: IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.

PubMed: 38007690
DOI: 10.1016/j.celrep.2023.113330

Experimental method

X-RAY DIFFRACTION (2.1 Å)