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Colby TD , Vanderveen K , Strickler MD , Markham GD , Goldstein BM
Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design
Proceedings of the National Academy of Sciences of the United States of America. 1999 Mar 30;96(7) :3531-3536
PMID: ISI:000079507900035   
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Abstract
Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step in the regulation of fell 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-Angstrom 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-3-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.
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Times Cited: 27 English Article 182PT PROC NAT ACAD SCI USA