9D3J

Structure of L9 Fab in complex with CSP_Res5-Y_mC2 Scaffold

Summary for 9D3J

• Entry DOI: 10.2210/pdb9d3j/pdb
• Descriptor: PfCSP_Res5-Y_mC2 Scaffold, L9 Fab heavy chain, L9 Fab light chain (3 entities in total)
• Functional Keywords: anti-malarial antibody complex with pfcsp scaffold, immune system
• Biological source: Plasmodium (Plasmodium); More
• Total number of polymer chains: 6
• Total formula weight: 108353.10

Authors

Jain, M.,Agrawal, S.,WIlson, I.A. (deposition date: 2024-08-10, release date: 2026-03-18, Last modification date: 2026-04-29)

Primary citation

Wu, N.R.,Castro, K.M.,Beutler, N.,Lee, W.H.,Raghavan, S.S.R.,Martin, G.M.,Jain, M.,Agrawal, S.,Liguori, A.,Kalyuzhniy, O.,Skog, P.D.,Terada, S.,Lai, Y.C.,Ndihokubwayo, J.,Lu, D.,Eskandarzadeh, S.,Alavi, N.,Phelps, N.,Tingle, R.,Youhanna, J.E.,Amirzehni, S.,Rogers, T.F.,Burton, D.R.,Wilson, I.A.,Ward, A.B.,Correia, B.E.,Schief, W.R.
Deep learning-enabled scaffolding of spatial arrays of PfCSP epitopes.
Proc.Natl.Acad.Sci.USA, 123:e2521914123-e2521914123, 2026

PubMed Abstract: Malaria is a leading cause of disease in developing countries. The licensed malaria vaccine RTS,S/AS01 confers partial protection in part due to the elicitation of circumsporozoite protein (CSP) antibodies, of which those to the CSP repeat and junctional regions offer the most potent protection. Anti-repeat region antibodies, including the protective antibody L9, frequently develop mutations that promote inter-Fab contacts when bound to CSP in "spiral" quaternary structures. As a first step toward the design of immunogens that elicit L9-like antibodies, we utilized generative deep learning models to design epitope scaffolds that incorporated up to three junctional repeat epitopes with structural conformations and relative spatial orientations matching those of the multivalent complex of CSP bound to three copies of L9. Affinity and structural studies demonstrated accurate scaffolding of two epitopes with the intended relative orientation, and displacement of the third epitope, while maintaining inter-Fab contacts between L9 antibodies. In a mouse model of malaria liver invasion, immunization with nanoparticles displaying these scaffold immunogens inhibited liver invasion as potently as matched nanoparticles displaying a short junctional peptide but less potently than the same nanoparticles displaying longer junctional peptides. This study demonstrates a substantial advance for design of multiepitope scaffolds with predetermined relative epitope spatial positioning. The study also represents an initial step toward development of multiepitope immunogens to elicit antibodies that utilize homotypic interactions to bind pathogens in multivalent clusters.

PubMed: 41945436
DOI: 10.1073/pnas.2521914123

Experimental method

X-RAY DIFFRACTION (3.5 Å)