PMID- 10097070
OWN - NLM
STAT- MEDLINE
DCOM- 19990512
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 7
DP  - 1999 Mar 30
TI  - Crystal structure of human type II inosine monophosphate dehydrogenase:
      implications for ligand binding and drug design.
PG  - 3531-6
AB  - 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.
FAU - Colby, T D
AU  - Colby TD
AD  - Department of Biochemistry and Biophysics, University of Rochester Medical
      Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
FAU - Vanderveen, K
AU  - Vanderveen K
FAU - Strickler, M D
AU  - Strickler MD
FAU - Markham, G D
AU  - Markham GD
FAU - Goldstein, B M
AU  - Goldstein BM
LA  - eng
SI  - PDB/1B3O
PT  - Journal Article
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Ligands)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Organoselenium Compounds)
RN  - 0 (Protein Isoforms)
RN  - 0 (Recombinant Proteins)
RN  - 131-99-7 (Inosine Monophosphate)
RN  - 151868-71-2 (beta-methylene selenazole-4-carboxamide adenine dinucleotide)
RN  - 5843-59-4 (6-chloropurine 9-beta-D-ribofuranosyl 5'-monophosphate)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - EC 1.1.1.205 (IMP Dehydrogenase)
SB  - IM
MH  - Adenosine Diphosphate/analogs & derivatives/chemistry/metabolism
MH  - Amino Acid Sequence
MH  - Antineoplastic Agents/chemical synthesis/chemistry
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Drug Design
MH  - Humans
MH  - IMP Dehydrogenase/antagonists & inhibitors/*chemistry/*metabolism
MH  - Immunosuppressive Agents/chemical synthesis/chemistry
MH  - Inosine Monophosphate/analogs & derivatives/chemistry/metabolism
MH  - Ligands
MH  - Macromolecular Substances
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Organoselenium Compounds/chemistry/metabolism
MH  - Protein Isoforms/chemistry/metabolism
MH  - Protein Structure, Secondary
MH  - Recombinant Proteins/antagonists & inhibitors/chemistry/metabolism
PMC - PMC22327
EDAT- 1999/03/31 00:00
MHDA- 1999/03/31 00:01
CRDT- 1999/03/31 00:00
PHST- 1999/03/31 00:00 [pubmed]
PHST- 1999/03/31 00:01 [medline]
PHST- 1999/03/31 00:00 [entrez]
AID - 10.1073/pnas.96.7.3531 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3531-6. doi: 10.1073/pnas.96.7.3531.