Next Article in Journal
Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo
Next Article in Special Issue
Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction?
Previous Article in Journal
Longitudinal Assessment of Antimicrobial Susceptibility among Gram-Negative and Gram-Positive Organisms Collected from Italy as Part of the Tigecycline Evaluation and Surveillance Trial between 2004 and 2011
Article Menu

Export Article

Open AccessArticle
Pharmaceuticals 2013, 6(11), 1407-1428; doi:10.3390/ph6111407

Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery

1
School of Computational Sciences and Crean School of Health and Life Sciences, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA
2
Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
*
Author to whom correspondence should be addressed.
Received: 29 July 2013 / Revised: 30 October 2013 / Accepted: 5 November 2013 / Published: 11 November 2013
(This article belongs to the Special Issue Allosteric Modulators)
View Full-Text   |   Download PDF [879 KB, uploaded 11 November 2013]   |  

Abstract

A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4) kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock) kinase from the system during client loading (release) stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.
Keywords: molecular chaperones; protein kinases; protein docking; protein-protein interactions; allosteric binding sites; drug discovery molecular chaperones; protein kinases; protein docking; protein-protein interactions; allosteric binding sites; drug discovery
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Lawless, N.; Blacklock, K.; Berrigan, E.; Verkhivker, G. Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery. Pharmaceuticals 2013, 6, 1407-1428.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top