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PDBsum entry 1urc
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Transferase/inhibitor
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PDB id
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1urc
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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, Biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-Dependent kinase complexes.
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Authors
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M.J.Andrews,
C.Mcinnes,
G.Kontopidis,
L.Innes,
A.Cowan,
A.Plater,
P.M.Fischer.
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Ref.
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Org Biomol Chem, 2004,
2,
2735-2741.
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PubMed id
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Abstract
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Inhibition of cyclin A- and cyclin E-associated cyclin-dependent kinase-2 (CDK2)
activities is an effective way of selective induction of apoptotic cell death
via the E2F pathway in tumour cells. The cyclin groove recognition motif (CRM)
in the natural CDK-inhibitory (CDKI) tumour suppressor protein p27KIP1 was used
as the basis for the design and synthesis of a series of cyclic peptides whose
biological activity and structural characterisation by NMR and X-ray
crystallography is reported. Whereas linear p27KIP1 sequence peptides were
comparatively ineffective, introduction of side chain-to-tail constraints was
found to be productive. An optimal macrocyclic ring size for the conformational
constraint was determined, mimicking the intramolecular H-bonding system of p27.
Molecular dynamics calculations of various macrocycles suggested a close
correlation between ring flexibility and biological activity. Truncated
inhibitor peptide analogues also confirmed the hypothesis that introduction of a
cyclic conformational constraint is favourable in terms of affinity and potency.
The structural basis for the potency increase in cyclic versus linear peptides
was demonstrated through the determination and interpretation of X-ray crystal
structures of complexes between CDK2/cylin A (CDK2A) and a constrained
pentapeptide.
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