1b3o
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TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE
OverviewOverview
Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step, in the regulation of cell growth and differentiation. This step is the, NAD-dependent oxidation of inosine 5' monophosphate (IMP) to xanthosine 5', monophosphate, the rate-limiting step in the synthesis of the guanine, nucleotides. Two isoforms of IMPDH have been identified, one of which, (type II) is significantly up- regulated in neoplastic and differentiating, cells. As such, it has been identified as a major target in antitumor and, immunosuppressive drug design. We present here the 2.9-A structure of a, ternary complex of the human type II isoform of IMPDH. The complex, contains the substrate analogue 6-chloropurine riboside 5'-monophosphate, (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine, dinucleotide, the selenium derivative of the active metabolite of the, antitumor drug tiazofurin. The enzyme forms a homotetramer, with the, dinucleotide binding at the monomer-monomer interface. The 6, chloro-substituted purine base is dehalogenated, forming a covalent adduct, at C6 with Cys-331. The dinucleotide selenazole base is stacked against, the 6-Cl-IMP purine ring in an orientation consistent with the B-side, stereochemistry of hydride transfer seen with NAD. The adenosine end of, the ligand interacts with residues not conserved between the type I and, type II isoforms, suggesting strategies for the design of isoform-specific, agents.
About this StructureAbout this Structure
1B3O is a Single protein structure of sequence from Homo sapiens with CPR, SAE and UNX as ligands. Active as IMP dehydrogenase, with EC number 1.1.1.205 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design., Colby TD, Vanderveen K, Strickler MD, Markham GD, Goldstein BM, Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3531-6. PMID:10097070
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