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PDBsum entry 1ol2
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Transferase/transferase inhibitor
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PDB id
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1ol2
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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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Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange.
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Authors
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G.Kontopidis,
M.J.Andrews,
C.Mcinnes,
A.Cowan,
H.Powers,
L.Innes,
A.Plater,
G.Griffiths,
D.Paterson,
D.I.Zheleva,
D.P.Lane,
S.Green,
M.D.Walkinshaw,
P.M.Fischer.
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Ref.
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Structure, 2003,
11,
1537-1546.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity
through blocking of the substrate recognition site in the cyclin A subunit has
been demonstrated to be an effective method for inducing apoptosis in tumor
cells. We have used the cyclin binding motif (CBM) present in the tumor
suppressor proteins p21(WAF1) and p27(KIP1) as a template to optimize the
minimal sequence necessary for CDK2/CA inhibition. A series of peptides were
prepared, containing nonnatural amino acids, which possess nano- to micromolar
CDK2-inhibitory activity. Here we present X-ray structures of the protein
complex CDK2/CA, together with the cyclin groove-bound peptides
H-Ala-Ala-Abu-Arg-Ser-Leu-Ile-(p-F-Phe)-NH(2) (peptide 1),
H-Arg-Arg-Leu-Ile-Phe-NH(2) (peptide 2), Ac-Arg-Arg-Leu-Asn-(m-Cl-Phe)-NH(2)
(peptide 3), H-Arg-Arg-Leu-Asn-(p-F-Phe)-NH(2) (peptide 4), and
H-Cit-Cit-Leu-Ile-(p-F-Phe)-NH(2) (peptide 5). Some of the peptide complexes
presented here were obtained through the novel technique of ligand exchange
within protein crystals. This method may find general application for obtaining
complex structures of proteins with surface-bound ligands.
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Figure 3.
Figure 3. The Electron Density Maps of Peptides 1-5The
2F[o] - 1F[c] maps are contoured at a level corresponding to 1.2
s for the peptides bound to the nonoccluded cyclin groove.(A)
Superimposition of the structures of peptide 2 in the free
(yellow) and partially occluded (green) CBG shows the
differences of the two copies of the peptide.(B) Overlay of the
bound conformations of peptides 1 (gray), 2 (green), 3 (red), 4
(CPK coloring), and 5 (magenta).
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2003,
11,
1537-1546)
copyright 2003.
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