Solution structure of p21(Waf1/Cip1/Sdi1) C-terminal domain bound to Cdk4

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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Y H Sung1, J Shin, J Shin

  • 1Department of Biochemistry and Protein-Network Research Center, College of Science, Yonsei University, Seoul, 120-749, Korea.

Journal of Biomolecular Structure & Dynamics
|January 16, 2002
PubMed

Insights

The p21 C-terminal domain (p21(CT)) acts as a potent Cdk4 inhibitor. Upon binding Cdk4, p21(CT) undergoes a conformational change, revealing a critical binding region essential for complex formation.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • p21(Waf1/Cip1/Sdi1) is a multifunctional protein acting as a tumor suppressor by inhibiting cyclin-dependent kinases (Cdks).
  • Recent studies suggest the C-terminal domain of p21 (p21(CT)) is crucial for inhibiting the Cyclin D1/Cdk4 complex.

Purpose of the Study:

  • To determine the solution structures of the p21 C-terminal domain (p21(CT)) in its free and Cdk4-bound states.
  • To elucidate the structural basis for p21's inhibition and specificity towards Cdk4.

Main Methods:

  • 2D transferred NOE spectroscopy was employed to study the protein structures.
  • Dynamical simulated annealing calculations were used to refine the structural models.

Main Results:

  • The p21(CT) peptide is flexible in its free state but becomes well-structured upon binding to Cdk4.
  • A significant conformational change in p21(CT) occurs upon Cdk4 complexation.
  • The D(149)FYHSKRR(156) region of p21 was identified as critical for Cdk4 binding.
  • Hydrophobic interactions are indicated as the primary driving force for p21-Cdk4 complex formation.

Conclusions:

  • p21(CT) undergoes an extensive conformational change upon binding Cdk4, contributing to its inhibitory function.
  • This structural plasticity may explain the specificity and inhibition mechanisms of p21 with different cyclin-Cdk complexes.
  • The identified binding region and hydrophobic interactions provide insights into the molecular mechanism of p21-Cdk4 inhibition.

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