2xu0

Crystal structure of the NTS-DBL1(alpha-1) domain of the Plasmodium falciparum membrane protein 1 (PfEMP1) from the varO strain.

spinqualitylabelsall models 2xu0, resolution 2.06Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2xu0 is a 1 chain structure with sequence from Plafp. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MG, PRO Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The human malaria parasite Plasmodium falciparum can cause infected red blood cells (iRBC) to form rosettes with uninfected RBC, a phenotype associated with severe malaria. Rosetting is mediated by a subset of the Plasmodium falciparum membrane protein 1 (PfEMP1) variant adhesins expressed on the infected host-cell surface. Heparin and other sulfated oligosaccharides, however, can disrupt rosettes, suggesting that therapeutic approaches to this form of severe malaria are feasible. We present a structural and functional study of the N-terminal domain of PfEMP1 from the VarO variant comprising the N-terminal segment (NTS) and the first DBL domain (DBL1alpha(1)), which is directly implicated in rosetting. We demonstrate that NTS-DBL1alpha(1)-VarO binds to RBC and that heparin inhibits this interaction in a dose-dependent manner, thus mimicking heparin-mediated rosette disruption. We have determined the crystal structure of NTS-DBL1alpha(1), showing that NTS, previously thought to be a structurally independent component of PfEMP1, forms an integral part of the DBL1alpha domain. Using mutagenesis and docking studies, we have located the heparin-binding site, which includes NTS. NTS, unique to the DBL alpha-class domain, is thus an intrinsic structural and functional component of the N-terminal VarO domain. The specific interaction observed with heparin opens the way for developing antirosetting therapeutic strategies. Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition.,Juillerat A, Lewit-Bentley A, Guillotte M, Gangnard S, Hessel A, Baron B, Vigan-Womas I, England P, Mercereau-Puijalon O, Bentley GA Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5243-8. Epub 2011 Mar 14. PMID:21402930 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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