Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design.
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.
Colby
T D
TD
Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Vanderveen
K
K
Strickler
M D
MD
Markham
G D
GD
Goldstein
B M
BM
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016566:Organoselenium Compounds / Q000737:chemistry / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D008024:Ligands; D046911:Macromolecular Substances; D016566:Organoselenium Compounds; D020033:Protein Isoforms; D011994:Recombinant Proteins; D007291:Inosine Monophosphate; C085446:beta-methylene selenazole-4-carboxamide adenine dinucleotide; C018488:6-chloropurine 9-beta-D-ribofuranosyl 5'-monophosphate; D000244:Adenosine Diphosphate; D007168:IMP Dehydrogenase