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PDBsum entry 3g33
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References listed in PDB file
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Key reference
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Title
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The structure of cdk4/cyclin d3 has implications for models of cdk activation.
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Authors
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T.Takaki,
A.Echalier,
N.R.Brown,
T.Hunt,
J.A.Endicott,
M.E.Noble.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
4171-4176.
[DOI no: ]
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PubMed id
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Abstract
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Cyclin-dependent kinase 4 (CDK4)/cyclin D complexes are expressed early in the
G(1) phase of the cell cycle and stimulate the expression of genes required for
G(1) progression by phosphorylation of the product of the retinoblastoma gene,
pRb. To elaborate the molecular pathway of CDK4 activation and substrate
selection we have determined the structure of nonphosphorylated CDK4/cyclin D3.
This structure of an authentic CDK/cyclin complex shows that cyclin binding may
not be sufficient to drive the CDK active site toward an active conformation.
Phosphorylated CDK4/cyclin D3 is active as a pRb kinase and is susceptible to
inhibition by p27(Kip1). Unlike CDK2/cyclin A, CDK4/cyclin D3 can be inactivated
by treatment with lambda-phosphatase, implying that phosphorylated T172 is
accessible to a generic phosphatase while bound to a cyclin. Taken together,
these results suggest that the structural mechanism of CDK4/cyclin D3 activation
differs markedly from that of previously studied CDK/cyclin complexes.
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Figure 1.
Structure and substrate selection in CDK4/cyclin D3. (A) The
fold of CDK4/cyclin D3 (left side) is compared with that of
CDK2/cyclin A in complex with a substrate peptide (PDB ID code
1QMZ; right side). Important structural and regulatory elements
referred to in the text are indicated on each structure and
correspond to the CDK N-lobe (light gray), the C-helix (cyan),
the CDK C-lobe (yellow), the activation segment (red), and the
cyclin subunit (green). (B) The activity of CDK4/cyclin D3
toward pRb family members highly depends on substrate
recruitment. See Results for details.
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Figure 2.
Comparison of the structures of monomeric CDK2, CDK4/cyclin
D3, and T160pCDK2/cyclin A. The 3 structures are viewed looking
down onto the CDK C-terminal domain from the N-terminal domain
and are colored according to the scheme used in Fig. 1. (A)
Monomeric CDK2. (B) CDK4/cyclin D3. (C) T160pCDK2/cyclin A. The
figure highlights the displacement of the CDK4/cyclin D3
activation segment away from the active conformation present in
T160pCDK2/cyclin A and its similarity to the structure of the
activation segment in monomeric CDK2 (monomeric T160pCDK2 PDB ID
code 1HCK).
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