7lkg

From Proteopedia

Crystal structure of PfCSP peptide 21 with vaccine-elicited human anti-malaria antibody m43.151

Structural highlights

7lkg is a 6 chain structure with sequence from Homo sapiens and Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.02Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CSP_PLAF7 Essential sporozoite protein (PubMed:29554084, PubMed:32150583). In the mosquito vector, required for sporozoite development in the oocyst, migration through the vector hemolymph and entry into the vector salivary glands (By similarity). In the vertebrate host, required for sporozoite migration through the host dermis and infection of host hepatocytes (PubMed:29554084, PubMed:32150583). Binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes (By similarity).[UniProtKB:P23093]^[1] ^[2] In the vertebrate host, binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes and is required for sporozoite invasion of the host hepatocytes.[UniProtKB:P23093]

Publication Abstract from PubMed

Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.

Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies.,Kratochvil S, Shen CH, Lin YC, Xu K, Nair U, Da Silva Pereira L, Tripathi P, Arnold J, Chuang GY, Melzi E, Schon A, Zhang B, Dillon M, Bonilla B, Flynn BJ, Kirsch KH, Kisalu NK, Kiyuka PK, Liu T, Ou L, Pancera M, Rawi R, Reveiz M, Seignon K, Wang LT, Waring MT, Warner J, Yang Y, Francica JR, Idris AH, Seder RA, Kwong PD, Batista FD Immunity. 2021 Dec 14;54(12):2859-2876.e7. doi: 10.1016/j.immuni.2021.10.017. , Epub 2021 Nov 16. PMID:34788599^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations

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References

↑ Tan J, Sack BK, Oyen D, Zenklusen I, Piccoli L, Barbieri S, Foglierini M, Fregni CS, Marcandalli J, Jongo S, Abdulla S, Perez L, Corradin G, Varani L, Sallusto F, Sim BKL, Hoffman SL, Kappe SHI, Daubenberger C, Wilson IA, Lanzavecchia A. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat Med. 2018 Mar 19. pii: nm.4513. doi: 10.1038/nm.4513. PMID:29554084 doi:http://dx.doi.org/10.1038/nm.4513
↑ Oyen D, Torres JL, Aoto PC, Flores-Garcia Y, Binter S, Pholcharee T, Carroll S, Reponen S, Wash R, Liang Q, Lemiale F, Locke E, Bradley A, King CR, Emerling D, Kellam P, Zavala F, Ward AB, Wilson IA. Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein. PLoS Pathog. 2020 Mar 9;16(3):e1008373. doi: 10.1371/journal.ppat.1008373. PMID:32150583 doi:http://dx.doi.org/10.1371/journal.ppat.1008373
↑ Kratochvil S, Shen CH, Lin YC, Xu K, Nair U, Da Silva Pereira L, Tripathi P, Arnold J, Chuang GY, Melzi E, Schön A, Zhang B, Dillon M, Bonilla B, Flynn BJ, Kirsch KH, Kisalu NK, Kiyuka PK, Liu T, Ou L, Pancera M, Rawi R, Reveiz M, Seignon K, Wang LT, Waring MT, Warner J, Yang Y, Francica JR, Idris AH, Seder RA, Kwong PD, Batista FD. Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies. Immunity. 2021 Dec 14;54(12):2859-2876.e7. PMID:34788599 doi:10.1016/j.immuni.2021.10.017