Cyclin-dependent kinase (Cdk) inhibitor p21Waf1/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 (p21CT) plays a key role as a potent Cdk4 inhibitor. We report here solution structures of p21CT for both the free and Cdk4-bound forms using 2D transferred NOE spectroscopy and dynamical simulated annealing calculations. Even though p21CT 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 p21CT experiences an extensive conformational change upon Cdk4 binding. This structural change of p21CT may suggest the molecular mechanism of p21 for specificity and inhibition mode to assemble different cyclin-Cdk complexes. Especially, our data suggests that the D149FYHSKRR156 region of p21 is critical for Cdk4 binding, indicating that the major driving force for complex originates from hydrophobic interaction between p21 and Cdk4.
Bibliographical noteFunding Information:
This work was supported by the Korea Science and Engineering Foundation (KOSEF) through the Center for Protein Network Research (PNRC) at Yonsei University (to W. Lee) and by Basic Science Research Institu te Program (BSRI-98-4410).
All Science Journal Classification (ASJC) codes
- Structural Biology
- Molecular Biology