Insights into the Allosteric Regulation of Human Hsp90 Revealed by NMR Spectroscopy DOI Creative Commons
Tjaša Goričan, Simona Golič Grdadolnik

Biomolecules, Journal Year: 2024, Volume and Issue: 15(1), P. 37 - 37

Published: Dec. 30, 2024

Human heat shock protein 90 (Hsp90) is one of the most important chaperones that play a role in late stages folding. Errors process chaperone cycle can lead to diseases such as cancer and neurodegenerative diseases. Therefore, activity Hsp90 must be carefully regulated. One possibilities allosteric regulation by its natural modulators-nucleotides, co-chaperones client proteins-and synthetic small-molecule modulators, those targeting middle domain or C-terminal (CTD) Hsp90. Since no experimentally determined structure modulator bound CTD human has yet been obtained, challenge for structure-based design modulators remains. Solution nuclear magnetic resonance (NMR) spectroscopy could utilized overcome these problems. The main aim this review article discuss how solution NMR techniques, especially protein-based, advanced isotope labeling proteins have used investigate cytosolic isoforms with modulators. This provides basis planning future experiments, gaining insights into sites mechanisms regulation.

Language: Английский

Advances in the structures, mechanisms and targeting of molecular chaperones DOI Creative Commons

Jinying Gu,

Yanyi He, Chenxi He

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 12, 2025

Abstract Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention protein misfolding and abnormal aggregation, modulation homeostasis, protection cells from damage under constantly changing environmental conditions. As understanding biological mechanisms molecular chaperones has increased, their link with occurrence progression disease suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances determining structures heat shock 90 (HSP90) chaperone system complexes. We also describe features shed light on complicated mechanism operates through interactions various co-chaperones cycles. In addition, how affect diseases by regulating pathogenic been thoroughly analyzed. Furthermore, focus to systematically discuss clinical drug design strategies preclinical stage. Recent studies have identified variety novel targeting systems compounds act different those traditional inhibitors. Therefore, as more developed, will significantly contribute discovery new potential drugs.

Language: Английский

Citations

1
(E)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1H-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer DOI Creative Commons

Gloria Ana,

Azizah M. Malebari, Sara Noorani

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 118 - 118

Published: Jan. 17, 2025

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These were designed hybrids the microtubule-targeting chalcones, indanones, aromatase inhibitor letrozole. Methods: A panel 29 synthesized examined by a preliminary screening estrogen receptor (ER) progesterone (PR)-positive MCF-7 cells together cell cycle analysis tubulin polymerization inhibition. Results: (E)-5-(3-(1H-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol 22b identified potent antiproliferative compound an IC50 value 0.39 mM cells, 0.77 triple-negative MDA-MB-231 0.37 leukemia HL-60 cells. In addition, demonstrated sub-micromolar range against NCI 60 line including prostate, melanoma, colon, leukemia, non-small lung cancers. G2/M phase arrest induction apoptosis inhibition demonstrated. Immunofluorescence studies confirmed that targeted while computational docking predicted binding conformations for colchicine site tubulin. Compound also selectively inhibited aromatase. Conclusions: Based on results obtained, these novel are suitable candidates further investigation cancer.

Language: Английский

Citations

0
Hsp90: Bringing It All Together DOI Creative Commons
Georgios I. Karras, Giorgio Colombo, Andrea N. Kravats

et al.

Cell Stress and Chaperones, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation function of Hsp90, which dwarfs sophistication other machines cell. Here, we propose four analogies to illustrate Hsp90's sophistication: a multifunctional Swiss Army knife, automobile engine its controls, switchboard acting as hub directing signals, orchestra conductor setting tempo symphony. Although each these represents some key Hsp90 activities, none them captures entirety complexity. Together, roles enable support both homeostasis differentiation, cellular stability adaptability. At 11th International Conference on Chaperone Machine, consensus was that understand this major guardian proteostasis, need study how many facets influence other. We hope will help conceptually integrate proteostasis field develop practical applications modulators.

Language: Английский

Citations

0
Recent progress and structural insights of potential Hsp90 inhibitors as anticancer agents DOI

Aastha Singh,

Satyabrata Maity,

Priya Devi

et al.

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Language: Английский

Citations

0
LMM Chemical Research with Document Retrieval DOI Creative Commons

Kevin Kawchak

Published: Aug. 13, 2024

Chemical research is more effectively progressed using Large Multimodal Models (LMMs) combined with Document Retrieval and recently published literature. The methods described here illustrate significant strides over previously tested Language Model (LLM) multi-document workflows for characterization assistance generating new reactions. Here, 3.5 Sonnet, ScholarGPT, ChatGPT 4o LMMs processed either 5 images or supplementary documents from leading 2024 journals. Each of the three models performed inference on a detailed prompt to produce response that included context attachments. In addition, were not provided which files contained answer. main findings Sonnet had an average score 9.8 images, while two judges awarded high scores (9.7, 9.4) ScholarGPT (9.5, document analysis. Judging was by human evaluator image uploads, processing evaluated Llama 3.1 405B Nemotron 4 340B LLMs correlated well improved explainability. Highlights include Sonnet's ability interpret Two-dimensional Nuclear Magnetic Resonance (2D NMR) spectrum accurately, along Judge 3.1's provide consistent formatted explanations. results shown help AI's continued revitalization established chemical field.

Language: Английский

Citations

1
First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo DOI Creative Commons
Jaka Dernovšek, Dunja Urbančič, Živa Zajec

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 153, P. 107850 - 107850

Published: Oct. 1, 2024

Language: Английский

Citations

1
Insights into the Allosteric Regulation of Human Hsp90 Revealed by NMR Spectroscopy DOI Creative Commons
Tjaša Goričan, Simona Golič Grdadolnik

Biomolecules, Journal Year: 2024, Volume and Issue: 15(1), P. 37 - 37

Published: Dec. 30, 2024

Human heat shock protein 90 (Hsp90) is one of the most important chaperones that play a role in late stages folding. Errors process chaperone cycle can lead to diseases such as cancer and neurodegenerative diseases. Therefore, activity Hsp90 must be carefully regulated. One possibilities allosteric regulation by its natural modulators-nucleotides, co-chaperones client proteins-and synthetic small-molecule modulators, those targeting middle domain or C-terminal (CTD) Hsp90. Since no experimentally determined structure modulator bound CTD human has yet been obtained, challenge for structure-based design modulators remains. Solution nuclear magnetic resonance (NMR) spectroscopy could utilized overcome these problems. The main aim this review article discuss how solution NMR techniques, especially protein-based, advanced isotope labeling proteins have used investigate cytosolic isoforms with modulators. This provides basis planning future experiments, gaining insights into sites mechanisms regulation.

Language: Английский

Citations

0