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https://www.readbyqxmd.com/read/29677383/effects-of-inhibitors-on-hsp90-s-conformational-dynamics-cochaperone-and-client-interactions
#1
Sonja Schmid, Markus Goetz, Thorsten Hugel
The molecular chaperone and heat-shock protein Hsp90 has become a central target in anti-cancer therapy. Nevertheless, the effect of Hsp90 inhibition is still not understood at the molecular level, preventing a truly rational drug design. Here we report on the effect of the most prominent drug candidates, namely radicicol, geldanamycin, derivatives of purine and novobiocin, on Hsp90's characteristic conformational dynamics and the binding of three interaction partners. Unexpectedly, the global opening and closing transitions are hardly affected by Hsp90 inhibitors...
April 20, 2018: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
https://www.readbyqxmd.com/read/29676157/high-throughput-assay-for-collagen-secretion-suggests-an-unanticipated-role-for-hsp90-in-collagen-production
#2
Madeline Y Wong, Ngoc Duc Doan, Andrew S DiChiara, Louis J Papa, Jaime H Cheah, Christian K Soule, Nicki Watson, John D Hulleman, Matthew D Shoulders
Collagen overproduction is a feature of fibrosis and cancer, while insufficient deposition of functional collagen molecules and/or the secretion of malformed collagen are common in genetic disorders like osteogenesis imperfecta. Collagen secretion is an appealing therapeutic target in these and other diseases, as secretion directly connects intracellular biosynthesis to collagen deposition and biological function in the extracellular matrix. However, small molecule and biological methods to tune collagen secretion are severely lacking...
April 20, 2018: Biochemistry
https://www.readbyqxmd.com/read/29674508/combined-braf-and-hsp90-inhibition-in-patients-with-unresectable-braf-v600e-mutant-melanoma
#3
Zeynep Eroglu, Yian Ann Chen, Geoffrey T Gibney, Jeffrey S Weber, Ragini R Kudchadkar, Nikhil I Khushalani, Joseph Markowitz, Andrew S Brohl, Leticia F Tetteh, Howida Ramadan, Gina Arnone, Jiannong Li, Xiuhua Zhao, Ritin Sharma, Lancia N F Darville, Bin Fang, Inna Smalley, Jane L Messina, John M Koomen, Vernon K Sondak, Keiran S M Smalley
PURPOSE: BRAF inhibitors are clinically active in patients with advanced BRAFV600 -mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. METHODS: Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO twice weekly) was investigated in 21 patients with advanced BRAFV600 -mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose...
April 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29665050/silence-of-hdac6-suppressed-esophageal-squamous-cell-carcinoma-proliferation-and-migration-by-disrupting-chaperone-function-of-hsp90
#4
Hua Tao, Yuan-Yuan Chen, Zong-Wen Sun, Hua-Lin Chen, Ming Chen
Esophageal carcinoma is aggressive in nature and its prognosis is largely dependent on the degree of invasion. Histone deacetylase 6 (HDAC6), as the most unique member of HDACs family, has the positive activity to promote initiation and progression of various cancers via targeting multiple non-histone proteins in cytoplasm. In this study, we found that HDAC6 was over-expressed in three esophageal cancer cell lines (KYSE140, KYSE170, KYSE180) when compared to non-carcinoma esophageal epithelial cell HEEC-1. Then two HDAC6 specific siRNAs and HDAC6 inhibitor tubastatin A greatly suppressed KYSE140 and KYSE180 cells proliferation and migration, and the inhibition of cell motility was accompanied by elevated acetylation of α-tubulin, a target of HDAC6...
April 17, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29664615/non-competitive-effect-of-gambogic-acid-displaces-fluorescence-labelled-atp-but-requires-atp-for-binding-to-hsp90-htpg
#5
Qing Yue, Frank Stahl, Oliver Plettenburg, Andreas Kirschning, Athanasia Warnecke, Carsten Zeilinger
The heat shock protein 90 (Hsp90) family plays a critical role in maintaining the homeostasis of the intracellular environment for human and prokaryotic cells. Hsp90 were identified as important target proteins for cancer and plant disease therapies. It was shown that gambogic acid (GBA) has the potential to inhibit human Hsp90. However, it is unknown, whether it is also able to act on the bacterial high temperature protein (HtpG) analogue. In this work, we screened GBA and nine other novel potential Hsp90 inhibitors using a miniaturized high throughput protein microarray-based assay and found that GBA shows an inhibitory effect on different Hsp90s after dissimilarity analysis of the protein sequence alignment...
April 17, 2018: Biochemistry
https://www.readbyqxmd.com/read/29663896/molecular-interaction-and-computational-analytical-studies-of-pinocembrin-for-its-antiangiogenic-potential-targeting-vegfr-2-a-persuader-of-metastasis
#6
Neha Sharma, Mala Sharma, Eram Shakeel, Qazi M Sajid Jamal, Mohammad A Kamal, Usman Sayeed, Mohammad K A Khan, Mohammad H Siddiqui, Jamal M Arif, Salman Akhtar
BACKGROUND: Designing a novel antagonist against VEGFR-2 is being applied currently to inhibit cancer growth and metastasis. Because of the unexpected side effects incurred by the contemporary anticancer medications, the focus has been laid towards identifying natural compounds that might carry the potential to inhibit tumor progression. VEGR-2 remains an important target for anticancer drug development as it is the master regulator of vascular growth. OBJECTIVE: The study focuses on virtual screening of compounds from plants of Asteraceae family that bears antiangiogenic potential and thus, inhibiting VEGFR-2 using a computational approach...
April 16, 2018: Medicinal Chemistry
https://www.readbyqxmd.com/read/29663867/coiled-coil-and-leucine-rich-repeat-domain-of-the-potyvirus-resistance-protein-pvr4-has-distinct-role-in-signaling-and-pathogen-recognition
#7
Saet-Byul Kim, Hye-Young Lee, Eun-Hye Choi, Eunsook Park, Jihyun Kim, Ki-Beom Moon, Hyun-Soon Kim, Doil Choi
The pepper Pvr4 encoding coiled-coil (CC) nucleotide-binding (NB) leucine-rich repeat (LRR) protein (CC-NLR) confer hypersensitive resistance (HR) to potyviruses, including Pepper mottle virus (PepMoV) by recognizing the viral avirulence protein, NIb. To figure out the Pvr4-mediated HR mechanism, we analyzed the signaling component genes and structure-function relationships of Pvr4 using chimeras and deletion mutants in Nicotiana benthamiana. Molecular chaperone components including HSP90, SGT1 and RAR1 were required, while plant hormones and mitogen-activated protein (MAP) kinase signaling components had little effect on Pvr4-NIb-mediated HR cell death...
April 17, 2018: Molecular Plant-microbe Interactions: MPMI
https://www.readbyqxmd.com/read/29663854/cyclin-dependent-kinase-1-targeting-improves-sensitivity-to-radiation-in-braf-v600e-colorectal-carcinoma-cells
#8
Girolamo Spagnoletti, Valeria Li Bergolis, Annamaria Piscazzi, Francesca Giannelli, Valentina Condelli, Lorenza Sisinni, Giuseppe Bove, Giovanni Storto, Matteo Landriscina
OBJECTIVES: Preoperative chemoradiation is currently the standard of care in locally advanced rectal carcinoma, even though a subset of rectal tumors does not achieve major clinically meaningful responses upon neoadjuvant chemoradiation. At present, no molecular biomarkers are available to predict response to neoadjuvant chemoradiation and select resistant tumors willing more intense therapeutic strategies. Thus, BRAF mutational status was investigated for its role in favoring resistance to radiation in colorectal carcinoma cell lines and cyclin-dependent kinase 1 as a target to improve radiosensitivity in BRAF V600E colorectal tumor cells...
April 2018: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29662162/a-switch-point-in-the-molecular-chaperone-hsp90-responding-to-client-interaction
#9
Daniel Andreas Rutz, Qi Luo, Lee Freiburger, Tobias Madl, Ville R I Kaila, Michael Sattler, Johannes Buchner
Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. It has been established that conformational switch points exist in the N-terminal (Hsp90-N) and C-terminal (Hsp90-C) domains of Hsp90, however information for switch points in the large middle-domain (Hsp90-M) is scarce. Here we report on a tryptophan residue in Hsp90-M as a new type of switch point. Our study shows that this conserved tryptophan senses the interaction of Hsp90 with a stringent client protein and transfers this information via a cation-π interaction with a neighboring lysine...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29662061/rpap3-provides-a-flexible-scaffold-for-coupling-hsp90-to-the-human-r2tp-co-chaperone-complex
#10
Fabrizio Martino, Mohinder Pal, Hugo Muñoz-Hernández, Carlos F Rodríguez, Rafael Núñez-Ramírez, David Gil-Carton, Gianluca Degliesposti, J Mark Skehel, S Mark Roe, Chrisostomos Prodromou, Laurence H Pearl, Oscar Llorca
The R2TP/Prefoldin-like co-chaperone, in concert with HSP90, facilitates assembly and cellular stability of RNA polymerase II, and complexes of PI3-kinase-like kinases such as mTOR. However, the mechanism by which this occurs is poorly understood. Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29660399/cacybp-sip-a-hsp90-binding-chaperone-in-cellular-stress-response
#11
Agnieszka Góral, Katarzyna Bartkowska, Rouzanna L Djavadian, Anna Filipek
CacyBP/SIP interacts with Hsp90 and is able to protect proteins from denaturation and/or aggregation induced by elevated temperature. In this work we studied the influence of different stress factors on CacyBP/SIP level in HEp-2 cells. We have found that H2 O2 and radicicol treatment resulted in a significant increase (up to 40-50%) in the CacyBP/SIP level. We have also found that HEp-2 cells overexpressing CacyBP/SIP were more resistant to stress-induced death. Further studies have revealed that the Hsf1 transcription factor binds to the CacyBP/SIP gene promoter and up-regulates CacyBP/SIP expression under stress conditions...
April 13, 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29659649/systems-analysis-of-the-genetic-interaction-network-of-yeast-molecular-chaperones
#12
Kamran Rizzolo, Ashwani Kumar, Yoshito Kakihara, Sadhna Phanse, Zoran Minic, Jamie Snider, Igor Stagljar, Sandra Zilles, Mohan Babu, Walid A Houry
Molecular chaperones are typically promiscuous interacting proteins that function globally in the cell to maintain protein homeostasis. Recently, we had carried out experiments that elucidated a comprehensive interaction network for the core 67 chaperones and 15 cochaperones in the budding yeast Saccharomyces cerevisiae [Rizzolo et al., Cell Rep., 2017, 20, 2735-2748]. Here, the genetic (i.e. epistatic) interaction network obtained for chaperones was further analyzed, revealing that the global topological parameters of the resulting network have a more central role in mediating interactions in comparison to the rest of the proteins in the cell...
April 16, 2018: Molecular omics
https://www.readbyqxmd.com/read/29658791/high-throughput-gene-expression-profiles-to-define-drug-similarity-and-predict-compound-activity
#13
Hans De Wolf, Laure Cougnaud, Kirsten Van Hoorde, An De Bondt, Joerg K Wegner, Hugo Ceulemans, Hinrich Göhlmann
By adding biological information, beyond the chemical properties and desired effect of a compound, uncharted compound areas and connections can be explored. In this study, we add transcriptional information for 31K compounds of Janssen's primary screening deck, using the HT L1000 platform and assess (a) the transcriptional connection score for generating compound similarities, (b) machine learning algorithms for generating target activity predictions, and (c) the scaffold hopping potential of the resulting hits...
April 2018: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/29658585/inhibitors-of-heat-shock-protein-90-augment-endothelin%C3%A2-1%C3%A2-induced-heat-shock-protein-27-through-the-sapk-jnk-signaling-pathway-in-osteoblasts
#14
Kazuhiko Fujita, Takanobu Otsuka, Tetsu Kawabata, Go Sakai, Rie Matsushima-Nishiwaki, Osamu Kozawa, Haruhiko Tokuda
It has been previously reported that endothelin‑1 (ET‑1) stimulates the induction of heat shock protein (HSP) 27 through the activation of p38 mitogen‑activated protein (MAP) kinase and stress‑activated protein kinase/c‑Jun N‑terminal kinase (SAPK/JNK) in osteoblast‑like MC3T3‑E1 cells. The present study investigated whether HSP90, a high‑molecular‑weight HSP, was implicated in the ET‑1‑stimulated HSP27 induction in MC3T3‑E1 cells. The effects of HSP90 inhibitors on the induction of HSP27 were examined...
April 12, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29655319/molecular-dynamics-simulations-of-site-point-mutations-in-the-tpr-domain-of-cyclophilin-40-identify-conformational-states-with-distinct-dynamic-and-enzymatic-properties
#15
Mert Gur, Elizabeth A Blackburn, Jia Ning, Vikram Narayan, Kathryn L Ball, Malcolm D Walkinshaw, Burak Erman
Cyclophilin 40 (Cyp40) is a member of the immunophilin family that acts as a peptidyl-prolyl-isomerase enzyme and binds to the heat shock protein 90 (Hsp90). Its structure comprises an N-terminal cyclophilin domain and a C-terminal tetratricopeptide (TPR) domain. Cyp40 is overexpressed in prostate cancer and certain T-cell lymphomas. The groove for Hsp90 binding on the TPR domain includes residues Lys227 and Lys308, referred to as the carboxylate clamp, and is essential for Cyp40-Hsp90 binding. In this study, the effect of two mutations, K227A and K308A, and their combinative mutant was investigated by performing a total of 5...
April 14, 2018: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29651431/hsp90-inhibition-reduces-tlr5-surface-expression-and-nf-%C3%AE%C2%BA-b-activation-in-human-myeloid-leukemia-thp-1-cells
#16
Bon Hyang Na, Thi Xoan Hoang, Jae Young Kim
Tumors highly express active heat shock protein 90 (Hsp90), which is involved in tumor survival and progression. Enhanced Toll-like receptor (TLR) 5 expression and signaling were reported to be associated with acute myeloid leukemia. In the present study, we investigated the possible modulatory effects of Hsp90 inhibitors on TLR5 expression and signaling in the human myeloid leukemia cell line THP-1. Cells were pretreated with various concentrations of the Hsp90 inhibitor geldanamycin (GA) or the Hsp70 inhibitor VER155008, followed by stimulation with bacterial flagellin...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29650281/recent-developments-and-obstacles-in-the-treatment-of-melanoma-with-braf-and-mek-inhibitors
#17
REVIEW
Mohd Wahid, Arshad Jawed, Raju K Mandal, Sajad A Dar, Naseem Akhter, Pallavi Somvanshi, Farah Khan, Mohtashim Lohani, Mohammed Y Areeshi, Shafiul Haque
Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes, lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time...
May 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29648939/reversal-of-schistosome-resistance-in-biomphalaria-glabrata-by-heat-shock-may-be-dependent-on-snail-genotype
#18
John Sullivan
Several genes have recently been shown to affect the innate resistance of laboratory strains of Biomphalaria glabrata to infection with Schistosoma mansoni, including Hsp90, expression of which following a brief exposure to elevated temperature can interfere with resistance in juvenile BS-90 snails. Because a prior study failed to see a similar effect in adult snails, juvenile BS-90 snails were exposed to 10 or 50 miracidia following a 4.5 to 6-hr incubation at 33 C or 37 C. Snails were then monitored for production of secondary sporocysts or release of cercariae...
April 12, 2018: Journal of Parasitology
https://www.readbyqxmd.com/read/29627724/a-tumor-targeted-ganetespib-zinc-phthalocyanine-conjugate-for-synergistic-chemo-photodynamic-therapy
#19
Liangfeng Huang, Gaofei Wei, Xiaoqi Sun, Yali Jiang, Zeqian Huang, Yanjuan Huang, Yifeng Shen, Xiaoyu Xu, Yunhui Liao, Chunshun Zhao
Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan-ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation...
March 31, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29626131/pervasive-contingency-and-entrenchment-in-a-billion-years-of-hsp90-evolution
#20
Tyler N Starr, Julia M Flynn, Parul Mishra, Daniel N A Bolon, Joseph W Thornton
Interactions among mutations within a protein have the potential to make molecular evolution contingent and irreversible, but the extent to which epistasis actually shaped historical evolutionary trajectories is unclear. To address this question, we experimentally measured how the fitness effects of historical sequence substitutions changed during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae We found a pervasive influence of epistasis...
April 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
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