EMD-27786
Cryo-EM structure of 334 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
EMD-27786
Single-particle3.62 Å
Deposition: 05/08/2022Map released: 02/08/2023
Last modified: 13/11/2024
Sample Organism:
Homo sapiens,
Plasmodium falciparum
Sample: 334 Fab - rsCSP complex
Fitted models: 8dyy (Avg. Q-score: 0.505)
Deposition Authors: Martin GM, Ward AB
Sample: 334 Fab - rsCSP complex
Fitted models: 8dyy (Avg. Q-score: 0.505)
Deposition Authors: Martin GM, Ward AB
Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.
Martin GM,
Torres JL ,
Pholcharee T ,
Oyen D,
Flores-Garcia Y,
Gibson G ,
Moskovitz R,
Beutler N ,
Jung DD,
Copps J ,
Lee WH ,
Gonzalez-Paez G ,
Emerling D ,
MacGill RS ,
Locke E,
King CR,
Zavala F ,
Wilson IA ,
Ward AB
(2023) Nat Commun , 14 , 4546 - 4546
,
Pholcharee T ,
Oyen D,
Flores-Garcia Y,
Gibson G ,
Moskovitz R,
Beutler N ,
Jung DD,
Copps J ,
Lee WH ,
Gonzalez-Paez G ,
Emerling D ,
MacGill RS ,
Locke E,
King CR,
Zavala F ,
Wilson IA ,
Ward AB
(2023) Nat Commun , 14 , 4546 - 4546
Abstract:
The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.
The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.