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PDBsum entry 1eep
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Oxidoreductase
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PDB id
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1eep
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Contents |
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* Residue conservation analysis
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DOI no:
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Biochemistry
39:4533-4542
(2000)
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PubMed id:
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Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5'-monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by loop 6.
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F.M.McMillan,
M.Cahoon,
A.White,
L.Hedstrom,
G.A.Petsko,
D.Ringe.
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ABSTRACT
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The conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate
(XMP) is the committed and rate-limiting reaction in de novo guanine nucleotide
biosynthesis. Inosine 5'- monophosphate dehydrogenase (IMPDH) is the enzyme that
catalyzes the oxidation of IMP to XMP with the concomitant reduction of
nicotinamide adenine dinucleotide (from NAD(+) to NADH). Because of its critical
role in purine biosynthesis, IMPDH is a drug design target for anticancer,
antiinfective, and immunosuppressive chemotherapy. We have determined the
crystal structure of IMPDH from Borrelia burgdorferi, the bacterial spirochete
that causes Lyme disease, with a sulfate ion bound in the IMP phosphate binding
site. This is the first structure of IMPDH in the absence of substrate or
cofactor where the active-site loop (loop 6), which contains the essential
catalytic residue Cys 229, is clearly defined in the electron density. We report
that a seven residue region of loop 6, including Cys229, is tilted more than 6 A
away from its position in substrate- or substrate analogue-bound structures of
IMPDH, suggestive of a conformational change. The location of this loop between
beta6 and alpha6 links IMPDH to a family of beta/alpha barrel enzymes known to
utilize this loop as a functional lid during catalysis. Least-squares
minimization, root-mean-square deviation analysis, and inspection of the
molecular surface of the loop 6 region in the substrate-free B. burgdorferi
IMPDH and XMP-bound Chinese hamster IMPDH show that loop 6 follows a similar
pattern of hinged rigid-body motion and indicates that IMPDH may be using loop 6
to bind and sequester substrate and to recruit an essential catalytic residue.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.R.Gollapalli,
I.S.Macpherson,
G.Liechti,
S.K.Gorla,
J.B.Goldberg,
and
L.Hedstrom
(2010).
Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases.
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Chem Biol,
17,
1084-1091.
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I.S.Macpherson,
S.Kirubakaran,
S.K.Gorla,
T.V.Riera,
J.A.D'Aquino,
M.Zhang,
G.D.Cuny,
and
L.Hedstrom
(2010).
The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivity.
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J Am Chem Soc,
132,
1230-1231.
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PDB codes:
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F.Rao,
Y.Qi,
H.S.Chong,
M.Kotaka,
B.Li,
J.Li,
J.Lescar,
K.Tang,
and
Z.X.Liang
(2009).
The functional role of a conserved loop in EAL domain-based cyclic di-GMP-specific phosphodiesterase.
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J Bacteriol,
191,
4722-4731.
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J.J.Ruiz-Pernía,
M.Garcia-Viloca,
S.Bhattacharyya,
J.Gao,
D.G.Truhlar,
and
I.Tuñón
(2009).
Critical role of substrate conformational change in the proton transfer process catalyzed by 4-oxalocrotonate tautomerase.
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J Am Chem Soc,
131,
2687-2698.
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L.Hedstrom
(2009).
IMP dehydrogenase: structure, mechanism, and inhibition.
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Chem Rev,
109,
2903-2928.
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S.Wong,
and
M.P.Jacobson
(2008).
Conformational selection in silico: loop latching motions and ligand binding in enzymes.
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Proteins,
71,
153-164.
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A.Berchanski,
D.Segal,
and
M.Eisenstein
(2005).
Modeling oligomers with Cn or Dn symmetry: application to CAPRI target 10.
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Proteins,
60,
202-206.
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G.André,
and
V.Tran
(2004).
Putative implication of alpha-amylase loop 7 in the mechanism of substrate binding and reaction products release.
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Biopolymers,
75,
95.
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N.N.Umejiego,
C.Li,
T.Riera,
L.Hedstrom,
and
B.Striepen
(2004).
Cryptosporidium parvum IMP dehydrogenase: identification of functional, structural, and dynamic properties that can be exploited for drug design.
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J Biol Chem,
279,
40320-40327.
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M.Garcia-Viloca,
D.G.Truhlar,
and
J.Gao
(2003).
Reaction-path energetics and kinetics of the hydride transfer reaction catalyzed by dihydrofolate reductase.
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Biochemistry,
42,
13558-13575.
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G.L.Prosise,
J.Z.Wu,
and
H.Luecke
(2002).
Crystal structure of Tritrichomonas foetus inosine monophosphate dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals a catalysis-dependent ion-binding site.
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J Biol Chem,
277,
50654-50659.
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PDB codes:
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G.P.Miller,
D.C.Wahnon,
and
S.J.Benkovic
(2001).
Interloop contacts modulate ligand cycling during catalysis by Escherichia coli dihydrofolate reductase.
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Biochemistry,
40,
867-875.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
