Structural highlights
Disease
IDHC_HUMAN Defects in IDH1 are involved in the development of glioma (GLM) [MIM:137800. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
Function
IDHC_HUMAN
Publication Abstract from PubMed
A point mutation in isocitrate dehydrogenase 1 (IDH1) and IDH2 is directly linked to the pathogenesis of certain types of tumors. To detect this mutation, several antibodies that can distinguish between mutant and wild-type enzymes have been established. One of which, MsMab-1, has a unique multi-specific character against several types of mutated IDH1/2. This promiscuous character is in remarkable contrast to the highly specific antigen recognition typically observed with a monoclonal antibody. We solved the crystal structure of MsMab-1 Fab fragment in complex with either IDH1 or IDH2-derived peptides. Based on the structure, it became clear that the peptide-binding pocket of the antibody is highly complementary to the core determinant shared between the IDH1 and IDH2, while leaving just enough space for the side chain of the pathogenic but not the wild-type amino acids located in the mutation position. Clarification of the molecular basis for the peculiar binding characteristics of MsMab-1 in atomic detail will help facilitating its diagnostic application, and may be used to develop better diagnostic reagents through structure-guided protein engineering.
Structural basis for multi-specific peptide recognition by the anti-IDH1/2 monoclonal antibody, MsMab-1.,Kitago Y, Kaneko MK, Ogasawara S, Kato Y, Takagi J Biochem Biophys Res Commun. 2016 Sep 23;478(3):1274-9. doi:, 10.1016/j.bbrc.2016.08.110. Epub 2016 Aug 20. PMID:27553275[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kitago Y, Kaneko MK, Ogasawara S, Kato Y, Takagi J. Structural basis for multi-specific peptide recognition by the anti-IDH1/2 monoclonal antibody, MsMab-1. Biochem Biophys Res Commun. 2016 Sep 23;478(3):1274-9. doi:, 10.1016/j.bbrc.2016.08.110. Epub 2016 Aug 20. PMID:27553275 doi:http://dx.doi.org/10.1016/j.bbrc.2016.08.110
