A5040066574- Heat shock proteins research
- Cancer-related Molecular Pathways
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Endoplasmic Reticulum Stress and Disease
- ATP Synthase and ATPases Research
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- Enzyme Structure and Function
- Protein Degradation and Inhibitors
- Mitochondrial Function and Pathology
- Chronic Lymphocytic Leukemia Research
- thermodynamics and calorimetric analyses
- Advanced Breast Cancer Therapies
- RNA Research and Splicing
- Cancer, Hypoxia, and Metabolism
- Cardiomyopathy and Myosin Studies
- Genomics and Chromatin Dynamics
- Biochemical and Molecular Research
- Prostate Cancer Treatment and Research
- Exercise and Physiological Responses
- Escherichia coli research studies
- X-ray Diffraction in Crystallography
- Chromatin Remodeling and Cancer
University of California, San Francisco
2016-2025
Anyang Eye Hospital
2025
Institute for Neurodegenerative Disorders
2018-2024
Southwest University
2022-2023
University of San Francisco
2023
German Center for Neurodegenerative Diseases
2023
Central South University
2021-2022
Guangxi Medical University
2022
Xiangya Hospital Central South University
2021
University of Nottingham
2012-2021
Abstract Disrupted homeostasis of the microtubule binding protein tau is a shared feature set neurodegenerative disorders known as tauopathies. Acetylation soluble an early pathological event in neurodegeneration. In this work, we find that large fraction neuronal degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, preferentially macroautophagy and endosomal microautophagy. Rerouting acetylated to these other autophagic pathways originates, part, from inhibitory effect...
Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival and reinstates apoptosis cancer cells. We designed series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached the C5-position pyrimidine or C4-thiazol moiety investigated their effects on potency selectivity. One most selective compounds, 12u inhibits IC(50) = 7 nM shows over 80-fold selectivity versus CDK2. X-ray...
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part elevated expression AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose has been correlated with therapeutic resistance and poor prognosis. In screen to identify small-molecule dual inhibitors both androgen-dependent androgen-independent gene signatures, we identified the chalcone C86. Binding studies using...
Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site Hsp70, interrupting its binding nucleotide-exchange factors (NEFs) promoting cell death in breast cancer lines. However, proof-of-concept molecules, such as JG-98, relatively modest potency (EC50 ≈ 0.7-0.4 μM) are rapidly metabolized animals. Here, we explored this chemical series through structure- property-based...
The spread of mosquito-borne Zika virus (ZIKV), which causes neurological disorders and microcephaly, highlights the need for countermeasures against sudden viral epidemics. Here, we tested concept that drugs targeting host proteostasis provide effective antivirals. We show different cytosolic Hsp70 isoforms are recruited to ZIKV-induced compartments required replication at pre- post-entry steps. Drugs significantly reduce ZIKV strains in human mosquito cells, including neural stem cells a...
// Elisabeth Walsby 1 , Guy Pratt 2 Hao Shao 3 Abdullah Y. Abbas Peter M. Fischer Tracey D. Bradshaw Paul Brennan Chris Fegan Shudong Wang 3,4 and Pepper Cardiff CLL Research Group, Institute of Cancer & Genetics, School Medicine, University, Heath Park, Cardiff, UK. CRUK for Studies, University Birmingham, Pharmacy Centre Biomolecular Sciences, Nottingham, 4 Medical South Australia, Adelaide, Australia. Correspondence: Pepper, email: Keywords : CLL, cdk9, synergy, MCL1 Received November 3,...
Modulation of energy metabolism with the small-molecule KHS101 promoted tumor-selective death human glioblastoma cells and reduced tumor growth in mice.
Abstract The mitochondrial chaperonin, heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in matrix, assisted by its co-chaperone mtHsp10. Despite essential role proteostasis, structural insights into how this chaperonin progresses through ATP-dependent client cycle are not clear. Here, we determined cryo-EM structures a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified three distinct states,...
Cyclin-dependent kinase 9/cyclin T, the protein heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design rationalize basis CDK9 selectivity, we have studied CDK-binding properties six different members 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series bind both CDK9/cyclin T CDK2/cyclin A. We find given CDK, melting...
Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released presence of androgens, enabling transactivation causing to become aggregation-prone. Here we show that these molecular recognize a region AR N-terminal domain (NTD), including FQNLF motif, interacts with ligand-binding (LBD) upon activation. This suggests competition between LBD for motif regulates We also that, while free NTD oligomerizes, binding increases its...
// Frankie Lam 1 , Abdullahi Y. Abbas 2 Hao Shao Theodosia Teo Julian Adams Peng Li Tracey D. Bradshaw Peter M. Fischer Elisabeth Walsby 3 Chris Pepper Yi Chen 4 Jian Ding and Shudong Wang 1,2 Centre for Drug Discovery Development, Sansom Institute Health Research School of Pharmacy Medical Sciences, University South Australia, Adelaide, Australia Biomolecular Nottingham, Park, United Kingdom Cardiff CLL Group, Cancer Genetics, Medicine, University, Cardiff, Shanghai Materia Medica, Chinese...
Hsp70 is a molecular chaperone that binds to "client" proteins and protects them from protein degradation. essential for the survival of many cancer cells, but it not yet clear which its clients are involved. Using structurally distinct chemical inhibitors, we found well-known related chaperone, Hsp90, strikingly responsive inhibition. Rather, appeared be important stability RIP1 (RIPK1) regulators: cIAP1/2 (BIRC1 BIRC3), XIAP, cFLIPS/L (CFLAR). These results suggest limits apoptosis...
Capillary electrophoresis (CE) has been identified as a useful platform for detecting, quantifying, and screening modulators of protein–protein interactions (PPIs). In this method, one protein binding partner is labeled with fluorophore, the partners are mixed, then, complex separated from free to allow direct determination bound ratios. Although it possesses many advantages PPI studies, method limited by need have separation conditions that both prevent adsorption capillary maintain during...
Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating relative contributions these 2 mechanisms requires fundamental knowledge how turnover WT mutant proteins regulated. We expressed several disease-causing mutations in primary neonatal rat ventricular cardiomyocytes. In...
Rationale: The double-layer sign of the anterior lens capsule during continuous curvilinear capsulorrhexis (CCC) in cataract surgery is a rare phenomenon. This case report highlights occurrence this and provides practical technique for managing it. Patient concerns: A 55-year-old Chinese woman presented with blurred vision her left eye. She had history nuclear sclerotic cataracts, but no abnormalities were noted preoperative evaluation. Diagnoses: Nuclear eye capsule. Interventions: During...
Mitochondrial chaperonin Heat Shock Protein 60 kDa (Hsp60) oversees the correct folding of client proteins in cooperation with Hsp10. Hsp60 monomers M first form 7-meric Single rings (S), which then pair into 14-meric Double (D) that accommodate clients their lumen. Recruitment 7 Hsp10 molecules per pole yields a sealed 28-meric Football-shaped complex (F). ATP hydrolysis each unit drives and F disassembly. The V72I mutation hereditary spastic paraplegia SPG13 impairs function despite being...
Protein–protein interactions (PPIs) are an important category of putative drug targets. Improvements in high-throughput screening (HTS) have significantly accelerated the discovery inhibitors for some categories PPIs. However, methods suitable multiprotein complexes (e.g. those composed three or more different components) been slower to emerge. Here, we explored approach that uses reconstituted (RMPCs). As a model system, chose heat shock protein 70 (Hsp70), which is ATP-dependent molecular...
The stress-induced chaperone protein Hsp70 enables the initiation and progression of many cancers, making it an appealing therapeutic target for development. Here, we show that cancer cells resistant to inhibitors in vitro remain sensitive them vivo, revealing pathogenic significance tumor stromal rather than as widely presumed. Using transgenic mouse models cancer, found expression host was essential support growth. Furthermore, genetic ablation or pharmacologic inhibition suppressed...