9ZNT

Cryo-EM structure of L9-yd19 in complex with Plasmodium falciparum circumsporozoite protein (PfCSP) 3D7 strain

Summary for 9ZNT

• Entry DOI: 10.2210/pdb9znt/pdb
• EMDB information: 74456
• Descriptor: Circumsporozoite protein, L9-yd19 heavy chain, L9-yd19 light chain (3 entities in total)
• Functional Keywords: anti-malarial, pfcsp, immune system
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 7
• Total formula weight: 118171.66

Authors

Tripathi, P.,Kwong, P.D. (deposition date: 2025-12-14, release date: 2026-10-21)

Primary citation

Chun, J.,Tripathi, P.,Flores-Garcia, Y.,Madan, B.,Lee, G.A.,Fahad, A.S.,Lei, H.,Teng, I.T.,Hurlburt, N.K.,Flynn, B.J.,Pancera, M.,Miura, K.,Zhou, T.,Idris, A.H.,Zavala, F.,Seder, R.A.,Kwong, P.D.,DeKosky, B.J.
Anti-malaria antibody engineering broadens recognition motifs and reveals new homotypic interactions that enhance protective breadth.
Nat Commun, 17:-, 2026

PubMed Abstract: The monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to a triplicate of NVDP-minor repeats on the P. falciparum circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a transgenic Plasmodium encoding chimeric CSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard complement of minor repeats. L9_yd19 also had high affinity against NANP-major repeats and was protective against transgenic Plasmodium expressing CSP with a NANP knock-in lacking NVDP. Cryo-EM studies revealed L9_yd19 to recognize PfCSP with two distinct homotypic interfaces, which combined to yield two trimeric layers of antibodies comprising asymmetric trimers that dimerized in a head-to-head fashion. These data reveal a new antibody mechanism that utilizes interfaces involving dual homotypic symmetry elements, a 2-fold and an asymmetric 3-fold, for improved malaria prevention.

PubMed: 42660882
DOI: 10.1038/s41467-026-75840-w

Experimental method

ELECTRON MICROSCOPY (3.6 Å)