6x8p

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Crystal structure of 3D11 Fab in complex with Plasmodium berghei circumsporozoite protein NPND peptide

Structural highlights

6x8p is a 3 chain structure with sequence from Mus musculus and Plasmodium berghei ANKA. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.27Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CSP_PLABA Essential sporozoite protein (PubMed:6985745, PubMed:15630135, PubMed:16207248, PubMed:18005753, PubMed:21262960). In the mosquito vector, required for sporozoite development in the oocyst, migration through the vector hemolymph and entry into the vector salivary glands (PubMed:16207248, PubMed:21262960). In the vertebrate host, required for sporozoite migration through the host dermis and infection of host hepatocytes (PubMed:6985745, PubMed:15630135, PubMed:18005753, PubMed:21262960). Binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes (PubMed:18005753).^[1] ^[2] ^[3] ^[4] ^[5] 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.^[6] ^[7]

Publication Abstract from PubMed

Plasmodium sporozoites express circumsporozoite protein (CSP) on their surface, an essential protein that contains central repeating motifs. Antibodies targeting this region can neutralize infection, and the partial efficacy of RTS,S/AS01 - the leading malaria vaccine against P. falciparum (Pf) - has been associated with the humoral response against the repeats. Although structural details of antibody recognition of PfCSP have recently emerged, the molecular basis of antibody-mediated inhibition of other Plasmodium species via CSP binding remains unclear. Here, we analyze the structure and molecular interactions of potent monoclonal antibody (mAb) 3D11 binding to P. berghei CSP (PbCSP) using molecular dynamics simulations, X-ray crystallography, and cryoEM. We reveal that mAb 3D11 can accommodate all subtle variances of the PbCSP repeating motifs, and, upon binding, induces structural ordering of PbCSP through homotypic interactions. Together, our findings uncover common mechanisms of antibody evolution in mammals against the CSP repeats of Plasmodium sporozoites.

Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11.,Kucharska I, Thai E, Srivastava A, Rubinstein JL, Pomes R, Julien JP Elife. 2020 Nov 30;9:e59018. doi: 10.7554/eLife.59018. PMID:33253113^[8]

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

References

↑ Coppi A, Pinzon-Ortiz C, Hutter C, Sinnis P. The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion. J Exp Med. 2005 Jan 3;201(1):27-33. PMID:15630135 doi:10.1084/jem.20040989
↑ Wang Q, Fujioka H, Nussenzweig V. Mutational analysis of the GPI-anchor addition sequence from the circumsporozoite protein of Plasmodium. Cell Microbiol. 2005 Nov;7(11):1616-26. PMID:16207248 doi:10.1111/j.1462-5822.2005.00579.x
↑ Coppi A, Tewari R, Bishop JR, Bennett BL, Lawrence R, Esko JD, Billker O, Sinnis P. Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells. Cell Host Microbe. 2007 Nov 15;2(5):316-27. PMID:18005753 doi:10.1016/j.chom.2007.10.002
↑ Coppi A, Natarajan R, Pradel G, Bennett BL, James ER, Roggero MA, Corradin G, Persson C, Tewari R, Sinnis P. The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. J Exp Med. 2011 Feb 14;208(2):341-56. PMID:21262960 doi:10.1084/jem.20101488
↑ Yoshida N, Nussenzweig RS, Potocnjak P, Nussenzweig V, Aikawa M. Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science. 1980 Jan 4;207(4426):71-3. PMID:6985745 doi:10.1126/science.6985745
↑ Coppi A, Tewari R, Bishop JR, Bennett BL, Lawrence R, Esko JD, Billker O, Sinnis P. Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells. Cell Host Microbe. 2007 Nov 15;2(5):316-27. PMID:18005753 doi:10.1016/j.chom.2007.10.002
↑ Coppi A, Natarajan R, Pradel G, Bennett BL, James ER, Roggero MA, Corradin G, Persson C, Tewari R, Sinnis P. The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. J Exp Med. 2011 Feb 14;208(2):341-56. PMID:21262960 doi:10.1084/jem.20101488
↑ Kucharska I, Thai E, Srivastava A, Rubinstein JL, Pomès R, Julien JP. Structural ordering of the Plasmodium berghei circumsporozoite protein repeats by inhibitory antibody 3D11. Elife. 2020 Nov 30;9:e59018. PMID:33253113 doi:10.7554/eLife.59018