7K76

Crystal structure of MAD2-6 IgG Fab in complex with PfCSP N-terminal peptide.

Summary for 7K76

• Entry DOI: 10.2210/pdb7k76/pdb
• Descriptor: Heavy chain of MAD2-6 IgG Fab, Light chain of MAD2-6 IgG Fab, PfCSP N-terminal peptide P17, ... (4 entities in total)
• Functional Keywords: malaria, circumsporozoite protein, n-terminal domain, region i, antibody, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 96661.21

Authors

Pholcharee, T.,Wilson, I.A. (deposition date: 2020-09-22, release date: 2021-06-23, Last modification date: 2024-04-03)

Primary citation

Tan, J.,Cho, H.,Pholcharee, T.,Pereira, L.S.,Doumbo, S.,Doumtabe, D.,Flynn, B.J.,Schon, A.,Kanatani, S.,Aylor, S.O.,Oyen, D.,Vistein, R.,Wang, L.,Dillon, M.,Skinner, J.,Peterson, M.,Li, S.,Idris, A.H.,Molina-Cruz, A.,Zhao, M.,Olano, L.R.,Lee, P.J.,Roth, A.,Sinnis, P.,Barillas-Mury, C.,Kayentao, K.,Ongoiba, A.,Francica, J.R.,Traore, B.,Wilson, I.A.,Seder, R.A.,Crompton, P.D.
Functional human IgA targets a conserved site on malaria sporozoites.
Sci Transl Med, 13:-, 2021

PubMed Abstract: Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as , is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

PubMed: 34162751
DOI: 10.1126/scitranslmed.abg2344

Experimental method

X-RAY DIFFRACTION (2.14 Å)