8UKH

Crystal structure of Plasmodium falciparum CelTOS in complex with antibody 4h12

Summary for 8UKH

• Entry DOI: 10.2210/pdb8ukh/pdb
• Descriptor: Cell traversal protein for ookinetes and sporozoites, 4h12 heavy chain, 4h12 light chain, ... (4 entities in total)
• Functional Keywords: transmission-blocking, membrane disruption, cell invasion
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 12
• Total formula weight: 259712.27

Authors

Tang, W.K.,Tolia, N.H.,Urusova, D. (deposition date: 2023-10-13, release date: 2024-09-11, Last modification date: 2024-10-23)

Primary citation

Tang, W.K.,Salinas, N.D.,Kolli, S.K.,Xu, S.,Urusova, D.V.,Kumar, H.,Jimah, J.R.,Subramani, P.A.,Ogbondah, M.M.,Barnes, S.J.,Adams, J.H.,Tolia, N.H.
Multistage protective anti-CelTOS monoclonal antibodies with cross-species sterile protection against malaria.
Nat Commun, 15:7487-7487, 2024

PubMed Abstract: CelTOS is a malaria vaccine antigen that is conserved in Plasmodium and other apicomplexan parasites and plays a role in cell-traversal. The structural basis and mechanisms of CelTOS-induced protective immunity to parasites are unknown. Here, CelTOS-specific monoclonal antibodies (mAbs) 7g7 and 4h12 demonstrated multistage activity, protecting against liver infection and preventing parasite transmission to mosquitoes. Both mAbs demonstrated cross-species activity with sterile protection against in vivo challenge with transgenic parasites containing either P. falciparum or P. vivax CelTOS, and with transmission reducing activity against P. falciparum. The mAbs prevented CelTOS-mediated pore formation providing insight into the protective mechanisms. X-ray crystallography and mutant-library epitope mapping revealed two distinct broadly conserved neutralizing epitopes. 7g7 bound to a parallel dimer of CelTOS, while 4h12 bound to a novel antiparallel dimer architecture. These findings inform the design of antibody therapies and vaccines and raise the prospect of a single intervention to simultaneously combat P. falciparum and P. vivax malaria.

PubMed: 39209843
DOI: 10.1038/s41467-024-51701-2

Experimental method

X-RAY DIFFRACTION (3.52 Å)