7rqr
Structure of chimeric antibody L9heavy_F10light with PfCSP peptide NANPNVDP
Structural highlights
FunctionCSP_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 PubMedL9 is a potent human monoclonal antibody (mAb) that preferentially binds two adjacent NVDP minor repeats and cross-reacts with NANP major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) on malaria-infective sporozoites. Understanding this mAb's ontogeny and mechanisms of binding PfCSP will facilitate vaccine development. Here, we isolate mAbs clonally related to L9 and show that this B cell lineage has baseline NVDP affinity and evolves to acquire NANP reactivity. Pairing the L9 kappa light chain (L9kappa) with clonally related heavy chains results in chimeric mAbs that cross-link two NVDPs, cross-react with NANP, and more potently neutralize sporozoites in vivo compared with their original light chain. Structural analyses reveal that the chimeric mAbs bound minor repeats in a type-1 beta-turn seen in other repeat-specific antibodies. These data highlight the importance of L9kappa in binding NVDP on PfCSP to neutralize sporozoites and suggest that PfCSP-based immunogens might be improved by presenting >/=2 NVDPs. The light chain of the L9 antibody is critical for binding circumsporozoite protein minor repeats and preventing malaria.,Wang LT, Hurlburt NK, Schon A, Flynn BJ, Flores-Garcia Y, Pereira LS, Kiyuka PK, Dillon M, Bonilla B, Zavala F, Idris AH, Francica JR, Pancera M, Seder RA Cell Rep. 2022 Feb 15;38(7):110367. doi: 10.1016/j.celrep.2022.110367. PMID:35172158[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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