9DX6

Crystal structure of Plasmodium vivax (Palo Alto) PvAMA1 in complex with human Fab 826827

Summary for 9DX6

• Entry DOI: 10.2210/pdb9dx6/pdb
• Descriptor: Apical merozoite protein 1, 826827 Fab Heavy chain, 826827 Fab Light chain, ... (4 entities in total)
• Functional Keywords: inhibitory antibody, complex, plasmodium vivax, cell invasion
• Biological source: Plasmodium vivax (malaria parasite P. vivax); More
• Total number of polymer chains: 3
• Total formula weight: 102899.05

Authors

Dietrich, M.H.,Tham, W.H.,Jung, N.C. (deposition date: 2024-10-10, release date: 2024-11-13, Last modification date: 2025-03-05)

Primary citation

Winnicki, A.C.,Dietrich, M.H.,Yeoh, L.M.,Carias, L.L.,Roobsoong, W.,Drago, C.L.,Malachin, A.N.,Redinger, K.R.,Feufack-Donfack, L.B.,Baldor, L.,Jung, N.C.,McLaine, O.S.,Skomorovska-Prokvolit, Y.,Orban, A.,Opi, D.H.,Kirtley, P.,Nielson, K.,Aleshnick, M.,Zanghi, G.,Rezakhani, N.,Vaughan, A.M.,Wilder, B.K.,Sattabongkot, J.,Tham, W.H.,Popovici, J.,Beeson, J.G.,Bosch, J.,King, C.L.
Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages.
Nat Commun, 15:10556-10556, 2024

PubMed Abstract: New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC of 0.3 - 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv.

PubMed: 39632799
DOI: 10.1038/s41467-024-53848-4

Experimental method

X-RAY DIFFRACTION (2.4 Å)