PDBsum entry 1mew

Oxidoreductase

PDB id: 1mew

Contents

Protein chain

344 a.a. *

Ligands

XMP

NAD

Metals

__K

Waters ×164

* Residue conservation analysis

PDB id:

1mew

Name:

Oxidoreductase

Title:

Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with xmp and NAD 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: 0.224 R-free: 0.246

Authors:

G.L.Prosise,H.Luecke

Key ref:

G.L.Prosise and H.Luecke (2003). Crystal structures of Tritrichomonasfoetus inosine monophosphate dehydrogenase in complex with substrate, cofactor and analogs: a structural basis for the random-in ordered-out kinetic mechanism. J Mol Biol, 326, 517-527. PubMed id: 12559919 DOI: 10.1016/S0022-2836(02)01383-9

Date:

08-Aug-02 Release date: 12-Aug-03

Protein chain

P50097  (IMDH_TRIFO) -  Inosine-5'-monophosphate dehydrogenase from Tritrichomonas foetus

Seq: 503 a.a.

Struc: 344 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.205 - Imp dehydrogenase.
• Pathway: AMP and GMP Biosynthesis
• Reaction: IMP + NAD⁺ + H2O = XMP + NADH + H⁺

IMP + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) + H2O = XMP (Bound ligand (Het Group name = XMP) corresponds exactly) + NADH + H(+)

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

reference

DOI no: 10.1016/S0022-2836(02)01383-9

J Mol Biol 326:517-527 (2003)

PubMed id: 12559919

Crystal structures of Tritrichomonasfoetus inosine monophosphate dehydrogenase in complex with substrate, cofactor and analogs: a structural basis for the random-in ordered-out kinetic mechanism.

G.L.Prosise, H.Luecke.

ABSTRACT

The enzyme inosine monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide biosynthesis. Because it is up-regulated in rapidly proliferating cells, human type II IMPDH is actively targeted for immunosuppressive, anticancer, and antiviral chemotherapy. The enzyme employs a random-in ordered-out kinetic mechanism where substrate or cofactor can bind first but product is only released after the cofactor leaves. Due to structural and kinetic differences between mammalian and microbial enzymes, most drugs that are successful in the inhibition of mammalian IMPDH are far less effective against the microbial forms of the enzyme. It is possible that with greater knowledge of the structural mechanism of the microbial enzymes, an effective and selective inhibitor of microbial IMPDH will be developed for use as a drug against multi-drug resistant bacteria and protists. The high-resolution crystal structures of four different complexes of IMPDH from the protozoan parasite Tritrichomonas foetus have been solved: with its substrate IMP, IMP and the inhibitor mycophenolic acid (MPA), the product XMP with MPA, and XMP with the cofactor NAD(+). In addition, a potassium ion has been located at the dimer interface. A structural model for the kinetic mechanism is proposed.

Selected figure(s)

Figure 1.
Figure 1. Ribbon diagram of the IMPDH tetramer viewed along the 4-fold axis. Each monomer displays the enzyme in one of the complexes presented here. At the top left, IMP is shown in green and at bottom left, the IMP-MPA complex is shown with MPA (orange). At the top right, the XMP-MPA complex is shown with XMP (blue). At the bottom right, the enzyme is in complex with XMP and the cofactor NAD^+ (yellow). Although the cofactor lies along the dimer interface, it does not make contact with the neighboring monomer. All molecular images were prepared with the program Deepview 3.7[37.] and rendered in POVRAY 3.5 beta (www.povray.org).

Figure 3.
Figure 3. A potassium ion (blue) was located at the dimer interface near the cofactor binding site. The carbon atoms of the neighboring catalytic monomer are colored gray and water molecules are shown as red spheres. The ion's hydrogen bonding partners and bond distances, clockwise from Asp264, are 2.94 Å and 2.49 Å, Asn460 (2.66 Å), Ser22 (2.57 Å), Gly20 (2.30 Å), and Phe260 (2.64 Å).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 326, 517-527) copyright 2003.

Figures were selected by an automated process.