4F3F: Crystal Structure of Msln7-64 Morab-009 FAB Complex

Citation:
Abstract
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.
PDB ID: 4F3FDownload
MMDB ID: 101247
PDB Deposition Date: 2012/5/9
Updated in MMDB: 2012/07 
Experimental Method:
x-ray diffraction
Resolution: 2.65  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit: trimeric; determined by author, and by software (PISA)
Molecular Components
Label Count Molecule
Proteins (3 molecules)
1
Morab-009 FAB Light Chain
Molecule annotation
1
Morab-009 FAB Heavy Chain
Molecule annotation
1
Mesothelin
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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