title: Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design.
abstract: The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD(+) revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD(+) phosphate. Neither feature is present in other d2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Hilbert
authors.affiliation: Division of Hematology, Oncology, and Palliative Care and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Grossman
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: William.Royer@umassmed.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Royer
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020816:Amino Acid Motifs; D020134:Catalytic Domain; D056970:Co-Repressor Proteins; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008715:Methionine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C014632:2-keto-4-methylthiobutyric acid; D008715:Methionine; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; C096794:C-terminal binding protein
keywords: Cancer target; Dehydrogenase; NADH; Transcriptional coregulator