1B3O

TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE

Summary for 1B3O

• Entry DOI: 10.2210/pdb1b3o/pdb
• Descriptor: PROTEIN (INOSINE MONOPHOSPHATE DEHYDROGENASE 2), 6-CHLOROPURINE RIBOSIDE, 5'-MONOPHOSPHATE, SELENAZOLE-4-CARBOXYAMIDE-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: dehydrogenase, impd, impdh, guanine nucleotide synthesis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 113917.74

Authors

Colby, T.D.,Vanderveen, K.,Strickler, M.D.,Goldstein, B.M. (deposition date: 1998-12-14, release date: 1999-04-12, Last modification date: 2024-12-25)

Primary citation

Colby, T.D.,Vanderveen, K.,Strickler, M.D.,Markham, G.D.,Goldstein, B.M.
Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design.
Proc.Natl.Acad.Sci.USA, 96:3531-3536, 1999

PubMed Abstract: 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.

PubMed: 10097070
DOI: 10.1073/pnas.96.7.3531

Experimental method

X-RAY DIFFRACTION (2.9 Å)