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PDBsum entry 1khf
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of human cytosolic phosphoenolpyruvate carboxykinase reveals a new gtp-Binding site.
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Authors
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P.Dunten,
C.Belunis,
R.Crowther,
K.Hollfelder,
U.Kammlott,
W.Levin,
H.Michel,
G.B.Ramsey,
A.Swain,
D.Weber,
S.J.Wertheimer.
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Ref.
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J Mol Biol, 2002,
316,
257-264.
[DOI no: ]
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PubMed id
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Abstract
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We report crystal structures of the human enzyme phosphoenolpyruvate
carboxykinase (PEPCK) with and without bound substrates. These structures are
the first to be determined for a GTP-dependent PEPCK, and provide the first view
of a novel GTP-binding site unique to the GTP-dependent PEPCK family. Three
phenylalanine residues form the walls of the guanine-binding pocket on the
enzyme's surface and, most surprisingly, one of the phenylalanine side-chains
contributes to the enzyme's specificity for GTP. PEPCK catalyzes the
rate-limiting step in the metabolic pathway that produces glucose from lactate
and other precursors derived from the citric acid cycle. Because the
gluconeogenic pathway contributes to the fasting hyperglycemia of type II
diabetes, inhibitors of PEPCK may be useful in the treatment of diabetes.
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Figure 2.
Figure 2. Interactions between the base and sugar of the
non-hydrolyzable GTP analog and the enzyme. The two water
molecules mediating hydrogen bonds to the protein are shown as
red spheres.
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Figure 3.
Figure 3. Comparison of the GTP-dependent and ATP-dependent
PEPCK structures. (a) Ribbon representation of the human enzyme
with metal ions and non-hydrolyzable GTP shown in ball-and-stick
form. (b) The E. coli enzyme with bound metal ions and ATP shown
in the same orientation to highlight the similarity of the fold.
(c) The active site of the human enzyme with bound
non-hydrolyzable GTP. The Mg and Mn ions are shown as purple
spheres and water molecules are shown as red spheres. (d)
Corresponding view of the active site of the E. coli enzyme
complexed with ATP taken from the Protein Data Bank, entry
1aq2[6]. A bound molecule of pyruvate marks the location of the
PEP site. The indicated torsion angle (O4'-C1'-N9-C4) is 57°
(syn) for bound ATP, versus 236° (anti) for the GTP bound to
the human enzyme. Atoms in the Figures are colored by type, with
C, N, O, S, and P atoms in green, dark blue, red, yellow, and
light blue, respectively.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2002,
316,
257-264)
copyright 2002.
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