8VDF

Cryo-EM structure of human monoclonal antibody C7 targeting IT4VAR22 CIDRa1.7 (PfEMP1 A)

Summary for 8VDF

• Entry DOI: 10.2210/pdb8vdf/pdb
• EMDB information: 43148
• Descriptor: Erythrocyte membrane protein 1, C7 Fab heavy chain, C7 Fab lamda chain (3 entities in total)
• Functional Keywords: malaria, pfemp1, human monoclonal antibodies, severe malaria., immune system
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum); More
• Total number of polymer chains: 3
• Total formula weight: 180517.46

Authors

Raghavan, S.S.R.,Ward, A.B. (deposition date: 2023-12-15, release date: 2024-10-02, Last modification date: 2024-12-18)

Primary citation

Reyes, R.A.,Raghavan, S.S.R.,Hurlburt, N.K.,Introini, V.,Bol, S.,Kana, I.H.,Jensen, R.W.,Martinez-Scholze, E.,Gestal-Mato, M.,Lopez-Gutierrez, B.,Sanz, S.,Bancells, C.,Fernandez-Quintero, M.L.,Loeffler, J.R.,Ferguson, J.A.,Lee, W.H.,Martin, G.M.,Theander, T.G.,Lusingu, J.P.A.,Minja, D.T.R.,Ssewanyana, I.,Feeney, M.E.,Greenhouse, B.,Ward, A.B.,Bernabeu, M.,Pancera, M.,Turner, L.,Bunnik, E.M.,Lavstsen, T.
Broadly inhibitory antibodies to severe malaria virulence proteins.
Nature, 636:182-189, 2024

PubMed Abstract: Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.

PubMed: 39567685
DOI: 10.1038/s41586-024-08220-3

Experimental method

ELECTRON MICROSCOPY (3.5 Å)