Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16(INK4a) Journal Article

  

Authors:	Russo, A. A.; Tong, L.; Lee, J. O.; Jeffrey, P. D.; Pavletich, N. P.
Article Title:	Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16(INK4a)
Abstract:	The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16(INK4a) tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16(INK4a) and to the related p19(INK4d) reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin- binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a an Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16(INK4a).
Keywords:	nonhuman; protein conformation; cell proliferation; animal cell; cell cycle proteins; cell cycle; protein p16; enzyme inhibition; protein binding; enzyme activity; structure-activity relationship; carcinogenesis; animalia; tumor suppressor gene; amino acid sequence; molecular sequence data; enzyme inhibitors; protein-serine-threonine kinases; escherichia coli; carrier proteins; recombinant proteins; binding site; models, molecular; crystallography, x-ray; binding sites; cyclin-dependent kinase inhibitor p16; adenosine triphosphate; protein structure; structure analysis; cyclin-dependent kinases; cyclins; cyclin dependent kinase; enzyme assay; genes, tumor suppressor; hexapoda; cyclin-dependent kinase 6; humans; priority journal; article; arachnida; cyclin-dependent kinase inhibitor p19
Journal Title:	Nature
Volume:	395
Issue:	6699
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	1998-09-17
Start Page:	237
End Page:	243
Language:	English
DOI:	10.1038/26155
PUBMED:	9751050
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0032541623&doi=10.1038%2f26155&partnerID=40&md5=655e7b831249d930e7313f8b00fb9930
Notes:	Article -- Export Date: 12 December 2016 -- Source: Scopus

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