4f3f

Crystal Structure of Msln7-64 MORAb-009 FAB complex

spinqualitylabelsall models 4f3f, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4f3f is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: PCA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MSLN_HUMAN Antibodies against MSLN are detected in patients with mesothelioma and ovarian cancer. Function MSLN_HUMAN Membrane-anchored forms may play a role in cellular adhesion. Megakaryocyte-potentiating factor (MPF) potentiates megakaryocyte colony formation in vitro. Publication Abstract from PubMed Mesothelin is a tumor differentiation antigen that is highly expressed in many epithelial cancers, with limited expression in normal human tissues. Binding of mesothelin on normal mesothelial cells lining the pleura or peritoneum to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. This binding can be prevented by MORAb-009, a humanized monoclonal antibody against mesothelin currently under clinical trials. We show here that MORAb-009 recognizes a non-linear epitope that is contained in the first 64-residue fragment of the mesothelin. We further demonstrate that the recognition is independent of glycosylation state of the protein but sensitive to the loss of a disulfide bond linking residues Cys-7 and Cys-31. The crystal structure of the complex between the mesothelin N-terminal fragment and Fab of MORAb-009 at 2.6 A resolution reveals an epitope encompassing multiple secondary structural elements of the mesothelin, including residues from helix alpha1, the loops linking helices alpha1 and alpha2, and between helices alpha4 and alpha5. The mesothelin fragment has a compact, right-handed superhelix structure consisting of five short helices and connecting loops. A residue essential for complex formation has been identified as Phe-22, which projects its side chain into a hydrophobic niche formed on the antibody recognition surface upon antigen-antibody contact. The overlapping binding footprints of both the monoclonal antibody and the cancer antigen CA-125 explains the therapeutic effect and provides a basis for further antibody improvement. Recognition of mesothelin by the therapeutic antibody MORAb-009: structural and mechanistic insights.,Ma J, Tang WK, Esser L, Pastan I, Xia D J Biol Chem. 2012 Sep 28;287(40):33123-31. Epub 2012 Jul 11. PMID:22787150 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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