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PDBsum entry 1vym
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DNA binding protein
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PDB id
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1vym
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References listed in PDB file
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Key reference
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Title
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Structural and biochemical studies of human proliferating cell nuclear antigen complexes provide a rationale for cyclin association and inhibitor design.
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Authors
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G.Kontopidis,
S.Y.Wu,
D.I.Zheleva,
P.Taylor,
C.Mcinnes,
D.P.Lane,
P.M.Fischer,
M.D.Walkinshaw.
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Ref.
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Proc Natl Acad Sci U S A, 2005,
102,
1871-1876.
[DOI no: ]
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PubMed id
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Abstract
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The interactions between the tumor suppressor protein p21WAF1 and the
cyclin-dependent kinase (CDK) complexes and with proliferating cell nuclear
antigen (PCNA) regulate and coordinate the processes of cell-cycle progression
and DNA replication. We present the x-ray crystal structure of PCNA complexed
with a 16-mer peptide related to p21 that binds with a Kd of 100 nM. Two
additional crystal structures of native PCNA provide previously undescribed
structures of uncomplexed human PCNA and show that significant changes on ligand
binding include rigidification of a number of flexible regions on the surface of
PCNA. In the competitive binding experiments described here, we show that a
20-mer sequence from p21 can be associated simultaneously with PCNA and
CDK/cyclin complexes. A structural model for this quaternary complex is
presented in which the C-terminal sequence of p21 acts like double-sided tape
and docks to both the PCNA and cyclin molecules. The quaternary complex shows
little direct interaction between PCNA and cyclin, giving p21 the role of an
adaptor molecule. Taken together, the biochemical and structural results
delineate a druggable inhibitor site on the surface of PCNA that may be
exploited in the design of peptidomimetics, which will act independently of
cyclin-groove inhibitors.
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Figure 4.
Fig. 4. Alignment of the PCNA structures in complex with
the p21-derived peptide 139GRKRRQTSMTDFYHSKRRLIFS160 (green)
with PCNA (cyan) (Protein Data Bank ID code 1AXC [PDB]
) and the PL peptide 1SAVLQKKITDYFHPKK16 (orange) with PCNA
(blue). Key interacting residues are labeled. The
phosphorylation site (S146) is highlighted, and the interaction
with D149 (D10) is shown (purple).
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Figure 6.
Fig. 6. Quaternary complex of CDK (green), cyclin (red),
and PCNA (blue). The model was produced by fitting together the
"RRLIF sequences" from the two crystal complexes [PCNA/p21
(Protein Data Bank ID code 1AXC [PDB]
) with the labeled peptide in yellow] and CDK/cyclin/RRLIF
(Protein Data Bank ID code 1OKV [PDB]
) with the peptide colored cyan. The exploded view shows that
the RRLIF conformations in the cyclin A- and PCNA-bound
structures are very similar.
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