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PDBsum entry 2iw8
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Contents |
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298 a.a.
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255 a.a.
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266 a.a.
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References listed in PDB file
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Key reference
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Title
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Dissecting the determinants of cyclin-Dependent kinase 2 and cyclin-Dependent kinase 4 inhibitor selectivity.
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Authors
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D.J.Pratt,
J.Bentley,
P.Jewsbury,
F.T.Boyle,
J.A.Endicott,
M.E.Noble.
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Ref.
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J Med Chem, 2006,
49,
5470-5477.
[DOI no: ]
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PubMed id
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Abstract
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Cyclin dependent kinases are a key family of kinases involved in cell cycle
regulation and are an attractive target for cancer chemotherapy. The roles of
four residues of the cyclin-dependent kinase active site in inhibitor
selectivity were investigated by producing cyclin-dependent kinase 2 mutants
bearing equivalent cyclin-dependent kinase 4 residues, namely F82H, L83V, H84D,
and K89T. Assay of the mutants with a cyclin-dependent kinase 4-selective
bisanilinopyrimidine shows that the K89T mutation is primarily responsible for
the selectivity of this compound. Use of the cyclin-dependent kinase 2-selective
6-cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) shows that K89T has
no role in the selectivity, while the remaining three mutations have a
cumulative influence. The results indicate that certain residues that are not
frequently considered in structure-aided kinase inhibitor design have an
important role to play.
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