 |
PDBsum entry 1mew
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
1mew
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
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.
|
|
|
Authors
|
|
G.L.Prosise,
H.Luecke.
|
|
|
Ref.
|
|
J Mol Biol, 2003,
326,
517-527.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
