Abstract
Understanding the mode of action of Hsp90 requires that molecular detail of its interactions with client proteins and co-chaperones are known. The structure determination of the N-terminal domain of Hsp90 / Hsp90β, proof that it is an ATPase, that this activity is regulated and the identification of cochaperones that facilitate Hsp90 function were landmarks towards understanding conformational changes in Hsp90 brought about by ATP, co-chaperones and client proteins. Sti1 and Cdc37 / p50, which associate with early Hsp90 complexes, were shown to be inhibitors of Hsp90 ATPase activity and therefore promote its ‘open’ state, whereas Sba1 / p23, which associates with mature complexes, inhibits ATPase activity and stabilises the ‘closed’ state. The isolation and characterisation of Aha1, the only known strong activator of Hsp90 ATPase activity, which promotes the ‘closed’ state of Hsp90, will also be of major importance in understanding Hsp90 function. The structure determination of the middle region of Hsp90 has shed further light on the complex ATP-cycle of Hsp90, identifying a catalytic loop, with key residues that are essential for ATP hydrolysis. These studies, together with biochemical ones, suggest that ATP hydrolysis, is dependent on a complex rate-limiting step, involving N-terminal dimerization and association of the middle region, and therefore the catalytic loop, of Hsp90 with the N-terminal domains. The structure of the middle region of Hsp90 will also accelerate our understanding of client protein interactions since this region is implicated in their recognition and in particular their active-site openings.
Keywords: Hsp90, cochaperones, N-terminal dimerization
Current Cancer Drug Targets
Title: Structure and Functional Relationships of Hsp90
Volume: 3 Issue: 5
Author(s): Chrisostomos Prodromou and Laurence H. Pearl
Affiliation:
Keywords: Hsp90, cochaperones, N-terminal dimerization
Abstract: Understanding the mode of action of Hsp90 requires that molecular detail of its interactions with client proteins and co-chaperones are known. The structure determination of the N-terminal domain of Hsp90 / Hsp90β, proof that it is an ATPase, that this activity is regulated and the identification of cochaperones that facilitate Hsp90 function were landmarks towards understanding conformational changes in Hsp90 brought about by ATP, co-chaperones and client proteins. Sti1 and Cdc37 / p50, which associate with early Hsp90 complexes, were shown to be inhibitors of Hsp90 ATPase activity and therefore promote its ‘open’ state, whereas Sba1 / p23, which associates with mature complexes, inhibits ATPase activity and stabilises the ‘closed’ state. The isolation and characterisation of Aha1, the only known strong activator of Hsp90 ATPase activity, which promotes the ‘closed’ state of Hsp90, will also be of major importance in understanding Hsp90 function. The structure determination of the middle region of Hsp90 has shed further light on the complex ATP-cycle of Hsp90, identifying a catalytic loop, with key residues that are essential for ATP hydrolysis. These studies, together with biochemical ones, suggest that ATP hydrolysis, is dependent on a complex rate-limiting step, involving N-terminal dimerization and association of the middle region, and therefore the catalytic loop, of Hsp90 with the N-terminal domains. The structure of the middle region of Hsp90 will also accelerate our understanding of client protein interactions since this region is implicated in their recognition and in particular their active-site openings.
Export Options
About this article
Cite this article as:
Prodromou Chrisostomos and Pearl H. Laurence, Structure and Functional Relationships of Hsp90, Current Cancer Drug Targets 2003; 3 (5) . https://dx.doi.org/10.2174/1568009033481877
DOI https://dx.doi.org/10.2174/1568009033481877 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Innovative Cancer Drug Targets: A New Horizon in Oncology
Cancer remains one of the most challenging diseases, with its complexity and adaptability necessitating continuous research efforts into more effective and targeted therapeutic approaches. Recent years have witnessed significant progress in understanding the molecular and genetic basis of cancer, leading to the identification of novel drug targets. These include, but ...read more
Role of Immune and Genotoxic Response Biomarkers in Tumor Microenvironment in Cancer Diagnosis and Treatment
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process of exploring and investigating the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Unraveling the Tumor Microenvironment and Potential Therapeutic Targets: Insights from Single-Cell Sequencing and Spatial Transcriptomics
This special issue will focus on unraveling the complexities of the tumor microenvironment (TME) and identifying key biomarkers for potential therapeutic targets using advanced multi-omics techniques, such as single-cell sequencing and spatial transcriptomics. We seek original research and comprehensive reviews that investigate the heterogeneity and dynamics of the TME, emphasizing ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Convenient and Efficient Method for Quality Control Analysis of 18F-Fluorocholine: For a Small Scale GMP-based Radiopharmaceuticals Laboratory Set-up
Current Radiopharmaceuticals Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis
Current Molecular Medicine New Indications for Established Drugs: Combined Tumor-Stroma-Targeted Cancer Therapy with PPARγ Agonists, COX-2 Inhibitors, mTOR Antagonists and Metronomic Chemotherapy
Current Cancer Drug Targets Targeting the G2/M Transition for Antitumor Therapy
Letters in Drug Design & Discovery Gene Therapy Approaches for the Prevention of Restenosis
Current Vascular Pharmacology Histone Acetylation / Deacetylation and Cancer: An “Open” and “Shut” Case?
Current Molecular Medicine Quality of Life of Children with Cerebral Palsy: A Cross-Sectional KIDSCREEN study in the Southern part of the Netherlands
CNS & Neurological Disorders - Drug Targets Fungal Proteins with Antiproliferative and Anticancer Activities
Protein & Peptide Letters Circular RNAs and Glioma: Small Molecule with Big Actions
Current Molecular Medicine Regulators of Stem Cells Proliferation in Tissue Regeneration
Current Stem Cell Research & Therapy Regulation of Eye Development by Protein Serine/Threonine Phosphatases-1 and -2A
Current Molecular Medicine New Medical Strategies for Midgut Carcinoids
Anti-Cancer Agents in Medicinal Chemistry Antiviral Drugs that Target Cellular Proteins May Play Major Roles in Combating HIV Resistance
Current Pharmaceutical Design IP6 in Cancer Therapy: Past, Present and Future
Current Cancer Therapy Reviews Differential Expression of miR-20a and miR-145 in Colorectal Tumors as Potential Location-specific miRNAs
MicroRNA Tumor-Targeting Peptides: Ligands for Molecular Imaging and Therapy
Anti-Cancer Agents in Medicinal Chemistry Good, Bad, Mobile Elements: Genome’s Most Successful “Parasites” as Emerging Players in Cell and Organismal Aging
Current Pharmaceutical Design EXTraordinary Bones: Functional and Genetic Analysis of the EXT Gene Family
Current Genomics Mouse Models of Primary Sjogren’s Syndrome
Current Pharmaceutical Design Metabolomics Applications in Precision Medicine: An Oncological Perspective
Current Topics in Medicinal Chemistry