7sg6

From Proteopedia

Structure of PfCSP peptide 21 with antibody CIS43_Var10

Structural highlights

7sg6 is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.55Å
Ligands:
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

The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.

Highly protective antimalarial antibodies via precision library generation and yeast display screening.,Banach BB, Tripathi P, Da Silva Pereira L, Gorman J, Nguyen TD, Dillon M, Fahad AS, Kiyuka PK, Madan B, Wolfe JR, Bonilla B, Flynn B, Francica JR, Hurlburt NK, Kisalu NK, Liu T, Ou L, Rawi R, Schon A, Shen CH, Teng IT, Zhang B, Pancera M, Idris AH, Seder RA, Kwong PD, DeKosky BJ J Exp Med. 2022 Aug 1;219(8):e20220323. doi: 10.1084/jem.20220323. Epub 2022 Jun , 23. PMID:35736810^[3]

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

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
↑ Banach BB, Tripathi P, Da Silva Pereira L, Gorman J, Nguyen TD, Dillon M, Fahad AS, Kiyuka PK, Madan B, Wolfe JR, Bonilla B, Flynn B, Francica JR, Hurlburt NK, Kisalu NK, Liu T, Ou L, Rawi R, Schön A, Shen CH, Teng IT, Zhang B, Pancera M, Idris AH, Seder RA, Kwong PD, DeKosky BJ. Highly protective antimalarial antibodies via precision library generation and yeast display screening. J Exp Med. 2022 Aug 1;219(8):e20220323. PMID:35736810 doi:10.1084/jem.20220323