Solution structure of p21(Waf1/Cip1/Sdi1) C-terminal domain bound to Cdk4.
Cyclin-dependent kinase (Cdk) inhibitor p21(Waf1/Cip1/Sdi1), a multifunctional protein, has a major role as tumor suppressor, mediating G1/S arrest through inhibition of Cdks. Recent biological studies of Cyclin D1/Cdk4 have proposed that p21 C-terminal domain (p21(CT)) plays a key role as a potent Cdk4 inhibitor. We report here solution structures of p21(CT) for both the free and Cdk4-bound forms using 2D transferred NOE spectroscopy and dynamical simulated annealing calculations. Even though p21(CT) peptide is very flexible in the free state, when it bound to Cdk4, the structure becomes well structured in the binding domain. Therefore we propose that p21(CT) experiences an extensive conformational change upon Cdk4 binding. This structural change of p21(CT) may suggest the molecular mechanism of p21 for specificity and inhibition mode to assemble different cyclin-Cdk complexes. Especially, our data suggests that the D(149)FYHSKRR(156) region of p21 is critical for Cdk4 binding, indicating that the major driving force for complex originates from hydrophobic interaction between p21 and Cdk4.
Sung
Y H
YH
Department of Biochemistry and Protein-Network Research Center, College of Science, Yonsei University, Seoul, 120-749, Korea.
Shin
J
J
Shin
J
J
Lee
W
W
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases