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DOI no:
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Proc Natl Acad Sci U S A
98:11218-11223
(2001)
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PubMed id:
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Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.
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M.Machius,
J.L.Chuang,
R.M.Wynn,
D.R.Tomchick,
D.T.Chuang.
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ABSTRACT
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Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate
the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of
these metabolites are implicated in disease states such as insulin-resistant
Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We
report a three-dimensional structure of a member of the mPK family, rat
branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a
characteristic nucleotide-binding domain and a four-helix bundle domain. These
two domains are reminiscent of modules found in protein histidine kinases
(PHKs), which are involved in two-component signal transduction systems. Unlike
PHKs, BCK dimerizes through direct interaction of two opposing
nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by
both potassium and magnesium. Binding of ATP induces disorder-order transitions
in a loop region at the nucleotide-binding site. These structural changes lead
to the formation of a quadruple aromatic stack in the interface between the
nucleotide-binding domain and the four-helix bundle domain, where they induce a
movement of the top portion of two helices. Phosphotransfer induces further
ordering of the loop region, effectively trapping the reaction product ADP,
which explains product inhibition in mPKs. The BCK structure is a prototype for
all mPKs and will provide a framework for structure-assisted inhibitor design
for this family of kinases.
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Selected figure(s)
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Figure 1.
Fig. 1. The mammalian protein kinase BCK. (A) Overall
view of the rat BCK dimer with the phosphotransfer reaction
product ADP shown as ball-and-stick model. Strands in the K
domain are not labeled. (B) Same as A, but rotated 90°
around the horizontal line. All figures were made with BOBSCRIPT
(46) and POVRAY (www.povray.org). (C) Sequence alignment of
mitochondrial protein kinases. Similar residues are colored
(yellow, hydrophobic; blue, basic; red, acidic; green, others).
Residues observed in the rat BCK structure are depicted below
the sequences (red, helices; blue, strands; gray, others); the
conserved nucleotide-binding motifs are indicated above the
consensus sequence. (D) Residues in the rat BCK dimer interface.
Water molecules participate in dimer formation only at the
periphery, but not in the core.
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Figure 2.
Fig. 2. Comparison of BCK with structurally related
kinases and ATPases. (A) Nucleotide-binding domain. BCK with
ADP, CheA "empty" (PDB ID code 1B3Q), and MutL with ADPNP (PDB
ID code 1B63). (B) B domain. BCK, CheA-HPt (PDB ID code 1i5n),
ArcB (PDB ID code 1A0B), and Ypd1p (PDB ID code 1C02).
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Figures were
selected
by an automated process.
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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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K.Akita,
Y.Fujimura,
G.Bajotto,
and
Y.Shimomura
(2009).
Inhibition of branched-chain alpha-ketoacid dehydrogenase kinase by thiamine pyrophosphate at different potassium ionic levels.
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Biosci Biotechnol Biochem, 73,
1189-1191.
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R.M.Wynn,
M.Kato,
J.L.Chuang,
S.C.Tso,
J.Li,
and
D.T.Chuang
(2008).
Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity.
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J Biol Chem, 283,
25305-25315.
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PDB codes:
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T.Green,
A.Grigorian,
A.Klyuyeva,
A.Tuganova,
M.Luo,
and
K.M.Popov
(2008).
Structural and functional insights into the molecular mechanisms responsible for the regulation of pyruvate dehydrogenase kinase 2.
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J Biol Chem, 283,
15789-15798.
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PDB codes:
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J.J.Petkowski,
M.Chruszcz,
M.D.Zimmerman,
H.Zheng,
T.Skarina,
O.Onopriyenko,
M.T.Cymborowski,
K.D.Koclega,
A.Savchenko,
A.Edwards,
and
W.Minor
(2007).
Crystal structures of TM0549 and NE1324--two orthologs of E. coli AHAS isozyme III small regulatory subunit.
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Protein Sci, 16,
1360-1367.
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PDB code:
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M.Kato,
J.L.Chuang,
S.C.Tso,
R.M.Wynn,
and
D.T.Chuang
(2005).
Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex.
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EMBO J, 24,
1763-1774.
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PDB codes:
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N.Fernandez-Fuentes,
A.Hermoso,
J.Espadaler,
E.Querol,
F.X.Aviles,
and
B.Oliva
(2004).
Classification of common functional loops of kinase super-families.
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Proteins, 56,
539-555.
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R.Hõrak,
H.Ilves,
P.Pruunsild,
M.Kuljus,
and
M.Kivisaar
(2004).
The ColR-ColS two-component signal transduction system is involved in regulation of Tn4652 transposition in Pseudomonas putida under starvation conditions.
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Mol Microbiol, 54,
795-807.
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T.E.Roche,
Y.Hiromasa,
A.Turkan,
X.Gong,
T.Peng,
X.Yan,
S.A.Kasten,
H.Bao,
and
J.Dong
(2003).
Essential roles of lipoyl domains in the activated function and control of pyruvate dehydrogenase kinases and phosphatase isoform 1.
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Eur J Biochem, 270,
1050-1056.
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E.Tan,
P.G.Besant,
and
P.V.Attwood
(2002).
Mammalian histidine kinases: do they REALLY exist?
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Biochemistry, 41,
3843-3851.
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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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308 a.a.
_CL
