Allosteric Modulators of HSP90 and HSP70: Dynamics Meets Function through Structure-Based Drug Design

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Heat shock proteins (HSP90 and HSP70) regulate client protein folding and activation through ATP hydrolysis.
• Understanding the interplay between ATP-dependent dynamics and client/cochaperone binding is key to harnessing their therapeutic potential.
• Allosteric modulators are valuable tools for dissecting chaperone function and dynamics.

Purpose of the Study:

• To review advances in the design of HSP90 and HSP70 allosteric modulators.
• To explore the use of these modulators as probes for understanding chaperone machinery.
• To highlight their potential as starting points for drug development.

Main Methods:

• Review of existing literature on HSP90 and HSP70 allosteric modulators.
• Analysis of inhibitors and activators in various biochemical and disease models.
• Discussion of structure-dynamics-function relationships.

Main Results:

• Allosteric modulators can selectively perturb HSP90/HSP70 activities, offering nuanced control over signaling pathways.
• These compounds provide molecular insights into chaperone complex assembly and regulation.
• Diverse modulators have been developed, acting as either inhibitors or activators.

Conclusions:

• Allosteric modulators are essential for deciphering the complex HSP90/HSP70 chaperone machinery.
• Targeting HSP90 and HSP70 with allosteric modulators shows promise for developing novel therapeutics.
• These approaches are particularly relevant for treating cancer and neurodegenerative diseases.