PDBsum entry: 1me7

Oxidoreductase

PDB id: 1me7

Contents

Protein chain

365 a.a. *

Ligands

RVP

MOA

Metals

_NA

__K

Waters ×120

* Residue conservation analysis

PDB id:

1me7

Name:

Oxidoreductase

Title:

Inosine monophosphate dehydrogenase (impdh) from tritrichomo with rvp and moa bound

Structure:

Inosine-5'-monophosphate dehydrogenase. Chain: a. Synonym: imp dehydrogenase, impdh. Engineered: yes

Source:

Tritrichomonas foetus. Organism_taxid: 5724. Gene: impdh. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.15Å R-factor: 0.233 R-free: 0.264

Authors:

G.L.Prosise,J.Wu,H.Luecke

Key ref:

G.L.Prosise et al. (2002). Crystal structure of Tritrichomonas foetus inosine monophosphate dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals a catalysis-dependent ion-binding site. J Biol Chem, 277, 50654-50659. PubMed id: 12235158 DOI: 10.1074/jbc.M208330200

Date:

08-Aug-02 Release date: 14-Jan-03

Protein chain

P50097  (IMDH_TRIFO) -  Inosine-5'-monophosphate dehydrogenase

Seq: 503 a.a.

Struc: 365 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.205 - Imp dehydrogenase.
• Pathway: AMP and GMP Biosynthesis
• Reaction: Inosine 5'-phosphate + NAD⁺ + H₂O = xanthosine 5'-phosphate + NADH

Inosine 5'-phosphate (Bound ligand (Het Group name = RVP) matches with 83.33% similarity) + NAD(+) + H(2)O = xanthosine 5'-phosphate + NADH

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Biological process: metabolic process (4 terms)
• Biochemical function: catalytic activity (8 terms)

reference

DOI no: 10.1074/jbc.M208330200

J Biol Chem 277:50654-50659 (2002)

PubMed id: 12235158

Crystal structure of Tritrichomonas foetus inosine monophosphate dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals a catalysis-dependent ion-binding site.

G.L.Prosise, J.Z.Wu, H.Luecke.

ABSTRACT

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in GMP biosynthesis. The resulting intracellular pool of guanine nucleotides is of great importance to all cells for use in DNA and RNA synthesis, metabolism, and signal transduction. The enzyme binds IMP and the cofactor NAD(+) in random order, IMP is converted to XMP, NAD(+) is reduced to NADH, and finally, NADH and then XMP are released sequentially. XMP is subsequently converted into GMP by GMP synthetase. Drugs that decrease GMP synthesis by inhibiting IMPDH have been shown to have antiproliferative as well as antiviral activity. Several drugs are in use that target the substrate- or cofactor-binding site; however, due to differences between the mammalian and microbial isoforms, most drugs are far less effective against the microbial form of the enzyme than the mammalian form. The high resolution crystal structures of the protozoan parasite Tritrichomonas foetus IMPDH complexed with the inhibitor ribavirin monophosphate as well as monophosphate together with a second inhibitor, mycophenolic acid, are presented here. These structures reveal an active site cation identified previously only in the Chinese hamster IMPDH structure with covalently bound IMP. This cation was not found previously in apo IMPDH, IMPDH in complex with XMP, or covalently bound inhibitor, indicating that the cation-binding site may be catalysis-dependent. A comparison of T. foetus IMPDH with the Chinese hamster and Streptococcus pyogenes structures reveals differences in the active site loop architecture, which contributes to differences in cation binding during the catalytic sequence and the kinetic rates between bacterial, protozoan, and mammalian enzymes. Exploitation of these differences may lead to novel inhibitors, which favor the microbial form of the enzyme.

Selected figure(s)

Figure 4.
Fig. 4. Ribbon diagram of the IMPDH tetramer viewed looking down the 4-fold axis. The enzyme is in complex with the inhibitor RMP (Corey-Pauling-Koltun (CPK) graphic) and a sodium ion (green). A potassium ion (blue) lies in the dimer interface near the cofactor-binding site. This image was made in Deepview (35) and rendered in POVRAY 3.5 beta (www.povray.org).

Figure 5.
Fig. 5. Composite annealed omit electron density maps at 1.9 Å resolution surrounding the inhibitor RMP. a, RMP-only co-crystal density contoured at 1.8 . The MPA-soaked RMP co-crystal structure (b) at 2.2 Å shows nearly complete density for MPA only when contoured at 0.5 despite soaking in saturating amounts of MPA. Soaking for longer periods did not improve occupancy.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 50654-50659) copyright 2002.

Figures were selected by an automated process.