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PDBsum entry 2w9z
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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 cdk4 in complex with a d-Type cyclin.
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Authors
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P.J.Day,
A.Cleasby,
I.J.Tickle,
M.O'Reilly,
J.E.Coyle,
F.P.Holding,
R.L.Mcmenamin,
J.Yon,
R.Chopra,
C.Lengauer,
H.Jhoti.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
4166-4170.
[DOI no: ]
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PubMed id
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Abstract
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The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex is a key regulator of the
transition through the G(1) phase of the cell cycle. Among the cyclin/CDKs, CDK4
and cyclin D1 are the most frequently activated by somatic genetic alterations
in multiple tumor types. Thus, aberrant regulation of the CDK4/cyclin D1 pathway
plays an essential role in oncogenesis; hence, CDK4 is a genetically validated
therapeutic target. Although X-ray crystallographic structures have been
determined for various CDK/cyclin complexes, CDK4/cyclin D1 has remained highly
refractory to structure determination. Here, we report the crystal structure of
CDK4 in complex with cyclin D1 at a resolution of 2.3 A. Although CDK4 is bound
to cyclin D1 and has a phosphorylated T-loop, CDK4 is in an inactive
conformation and the conformation of the heterodimer diverges from the
previously known CDK/cyclin binary complexes, which suggests a unique mechanism
for the process of CDK4 regulation and activation.
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Figure 1.
Ribbon diagram of the CDK4 (cyan)/cyclin D1 (orange)
heterodimer. (A) The N- and C-terminal lobes of the kinase are
labeled as are key secondary structural elements. (B) CDK7
(yellow) (Protein Data Bank ID code 1UA2) and CDK4 (cyan) (rmsd
1.053 Å). Both the αC-helix and T-loop of CDK7 adopt
inactive conformations that are similar to the conformations of
the equivalent secondary structural elements observed in CDK4.
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Figure 3.
Architecture of the engineered loop preceding the αC-helix
in the CDK4 (cyan)/cyclin D1 (orange) structure. (A) Akin to
CDK2 and CDK6 (see Fig. S4) the apex of the loop is stabilized
by hydrogen bonds from the loop main chain to a highly-conserved
lysine (Lys[D1]112) and glutamate (Glu[D1]141) on the cyclin.
The second glutamate (Glu[K4]44′) from the GE′E′G
insertion mimics the interactions formed by the glutamate in the
CDK6 structure. The loop is further stabilized by intramolecular
H-bonds, which are not observed in either the CDK2 or CDK6
structures. A cyclin D1 Lys[D1]112–Glu mutation results in
aberrant CDK4/cyclin D1 complex assembly and activation. (B)
Residues in the vicinity of cyclin D1 (orange) Lys[D1]114. The
Lys[D1]114–Glu mutation results in defective CDK4/cyclin D1
complex formation. Lys[D1]114 sits within an acidic environment
formed by Glu[D1]74, Glu[D1]75, Glu[D1]76, Asp[D1]159, and
Glu[D1]162. It would be anticipated that introduction of an
additional negative charge into this environment would be highly
destabilizing and significantly perturb correct CDK/cyclin
association.
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