Emerging functions of pseudoenzymes DOI Creative Commons

Timea Goldberg,

Anju Sreelatha

Biochemical Journal, Год журнала: 2023, Номер 480(10), С. 715 - 728

Опубликована: Май 19, 2023

As sequence and structural databases grow along with powerful analysis tools, the prevalence diversity of pseudoenzymes have become increasingly evident. Pseudoenzymes are present across tree life in a large number enzyme families. defined as proteins that lack conserved catalytic motifs based on analysis. However, some may migrated amino acids necessary for catalysis, allowing them to catalyze enzymatic reactions. Furthermore, retain several non-enzymatic functions such allosteric regulation, signal integration, scaffolding, competitive inhibition. In this review, we provide examples each mode action using pseudokinase, pseudophosphatase, pseudo ADP-ribosyltransferase We highlight methodologies facilitate biochemical functional characterization encourage further investigation burgeoning field.

Язык: Английский

Three Essential Resources to Improve Differential Scanning Fluorimetry (DSF) Experiments DOI Creative Commons
Taiasean Wu,

Joshua Yu,

Zachary J. Gale-Day

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2020, Номер unknown

Опубликована: Март 25, 2020

Abstract Differential Scanning Fluorimetry (DSF) is a method that enables rapid determination of protein’s apparent melting temperature (Tm ). Owing to its high throughput, DSF has found widespread application in fields ranging from structural biology chemical screening. Yet developed two opposing reputations: one as an indispensable laboratory tool probe protein stability, another frustrating platform often fails. Here, we aim reconcile these disparate reputations and help users perform more successful experiments with three resources: updated, interactive theoretical framework, practical tips, online data analysis. We anticipate resources, made available at DSFworld ( https://gestwickilab.shinyapps.io/dsfworld/ ), will broaden the utility DSF.

Язык: Английский

Процитировано

47
Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9 DOI Open Access
Seiko Yoshino, Takashi Yokoyama,

Yoshitaka Sunami

и другие.

Blood, Год журнала: 2020, Номер 137(1), С. 75 - 88

Опубликована: Июль 31, 2020

Язык: Английский

Процитировано

43
The Critical Role of TRIB2 in Cancer and Therapy Resistance DOI Open Access

Víctor Mayoral-Varo,

Lucía Jiménez, Wolfgang Link

и другие.

Cancers, Год журнала: 2021, Номер 13(11), С. 2701 - 2701

Опубликована: Май 30, 2021

The Tribbles pseudokinases family consists of TRIB1, TRIB2, TRIB3 and STK40 and, although evolutionarily conserved, they have distinctive characteristics. members are expressed in a context cell compartment-dependent manner. For example, TRIB1 TRIB2 potent oncogenic activities vertebrate cells. Since the identification proteins as modulators multiple signalling pathways, recent studies linked their expression with several pathologies, including cancer. act protein adaptors involved ubiquitin-proteasome degradation system, bridge gap between substrates E3 ligases. Between TRIB members, is most ancestral member family. homeostasis regulation C/EBPα, β-catenin TCF4. On other hand, interacts MAPKK, AKT NFkB proteins, survival, proliferation immune response. Here, we review characteristic features structure its role many cancer subtypes an emphasis on function therapy resistance melanoma, leukemia glioblastoma. strong evidence chemoresistance provides attractive opportunity for targeting TRIB2.

Язык: Английский

Процитировано

37
Looking lively: emerging principles of pseudokinase signaling DOI Creative Commons
Joshua B. Sheetz, Mark A. Lemmon

Trends in Biochemical Sciences, Год журнала: 2022, Номер 47(10), С. 875 - 891

Опубликована: Май 16, 2022

Язык: Английский

Процитировано

28
Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma DOI Creative Commons
Jia Wang,

Jie Zuo,

Alafate Wahafu

и другие.

CNS Neuroscience & Therapeutics, Год журнала: 2019, Номер 26(3), С. 297 - 308

Опубликована: Июль 18, 2019

Abstract Introduction Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults with poor survival due to acquired therapeutic resistance and rapid recurrence. Currently, standard clinical strategy for glioma includes maximum surgical resection, radiotherapy, temozolomide (TMZ) chemotherapy; however, median of patients GBM remains despite these comprehensive therapies. Therefore, identification new prognostic biomarkers urgently needed evaluate malignancy long‐term outcome glioma. Aims To further investigate potential targets GBM. Results In this study, we identified tribbles pseudokinase 2 (TRIB2) as one genes that correlated pathological classification, radioresistance, TMZ Additionally, expression mitogen‐activated protein kinase 1 (MAP3K1) showed a strong correlation TRIB2. Moreover, combined increase TRIB2 MAP3K1 was observed indicated prognosis Finally, enriched were shown be associated radiotherapy. Conclusion Combined elevation could novel outcomes

Язык: Английский

Процитировано

42
Target identification and validation of natural products with label-free methodology: A critical review from 2005 to 2020 DOI
Lingyun Dai, Zhijie Li, Dan Chen

и другие.

Pharmacology & Therapeutics, Год журнала: 2020, Номер 216, С. 107690 - 107690

Опубликована: Сен. 25, 2020

Язык: Английский

Процитировано

38
Recent Advances in c-Jun N-Terminal Kinase (JNK) Inhibitors DOI
Gang Li, Wenqing Qi, Xiaoxun Li

и другие.

Current Medicinal Chemistry, Год журнала: 2020, Номер 28(3), С. 607 - 627

Опубликована: Фев. 10, 2020

c-Jun N-Terminal Kinases (JNKs), members of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, play a key role in pathogenesis many diseases including cancer, inflammation, Parkinson’s disease, Alzheimer’s cardiovascular obesity, and diabetes. Therefore, JNKs represent new excellent target by therapeutic agents. Many JNK inhibitors based on different molecular scaffolds have been discovered past decade. However, only few them advanced to clinical trials. The major obstacle for development as agents is JNKisoform selectivity. In this review, we describe recent inhibitors, ATP competitive non-competitive (allosteric) bidentatebinding dual challenges, future direction potential

Язык: Английский

Процитировано

33
TRIB2 modulates proteasome function to reduce ubiquitin stability and protect liver cancer cells against oxidative stress DOI Creative Commons
Susu Guo, Yuxin Chen,

Yueyue Yang

и другие.

Cell Death and Disease, Год журнала: 2021, Номер 12(1)

Опубликована: Янв. 7, 2021

Abstract The regulation of homeostasis in the Ubiquitin (Ub) proteasome system (UPS) is likely to be important for development liver cancer. Tribbles homolog 2 (TRIB2) known affect Ub E3 ligases (E3s) However, whether TRIB2 regulates UPS other ways and relevant mechanisms are still unknown. Here, we reveal that decreased levels largely by stimulating degradation Ub. In proteasome, 20S subunit beta 5 (PSMB5) was critical function TRIB2, although it did not directly interact with TRIB2. poly (rC) binding protein (PCBP2), which identified mass spectrometry, interacted both PSMB5. PCBP2 a prerequisite induction PSMB5 activity levels. A significant correlation between revealed cancer specimens. Interestingly, suppressed K48-ubiquitination increase its level. Therefore, model showing cooperates stimulates reduce established. Additionally, reduction induced dependent on K48-ubiquitination. one possible downstream factors their interaction relied DQLVPD element KH3 domain PCBP2. This necessary maintain viability cells promote tumor growth. Mechanistically, glutathione peroxidase 4 functioned as terminal effectors protect from oxidative damage. Taken together, data indicate that, addition affecting E3s, plays role regulating modulating flux, targeting might helpful treatments enhancing damage therapeutic agents.

Язык: Английский

Процитировано

29
Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery DOI Creative Commons
Lingling Shen,

Jian Fang,

Lulu Liu

и другие.

Journal of Cheminformatics, Год журнала: 2024, Номер 16(1)

Опубликована: Март 21, 2024

Abstract We present a user-friendly molecular generative pipeline called Pocket Crafter, specifically designed to facilitate hit finding activity in the drug discovery process. This workflow utilized three-dimensional (3D) modeling method Pocket2Mol, for de novo design of molecules spatial perspective targeted protein structures, followed by filters chemical-physical properties and drug-likeness, structure–activity relationship analysis, clustering generate top virtual scaffolds. In our WDR5 case study, we acquired focused set 2029 compounds after searching within Novartis archived library based on Subsequently, experimentally profiled these compounds, resulting novel chemical scaffold series that demonstrated biochemical biophysical assays. Crafter successfully prototyped an effective end-to-end 3D chemistry-based exploration new scaffolds, which represents promising approach early identification.

Язык: Английский

Процитировано

5
ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1 DOI Creative Commons
Kathryn Balmanno, Andrew M. Kidger, Dominic P. Byrne

и другие.

Biochemical Journal, Год журнала: 2023, Номер 480(9), С. 587 - 605

Опубликована: Апрель 5, 2023

Innate or acquired resistance to small molecule BRAF MEK1/2 inhibitors (BRAFi MEKi) typically arises through mechanisms that sustain reinstate ERK1/2 activation. This has led the development of a range (ERKi) either inhibit kinase catalytic activity (catERKi) additionally prevent activating pT-E-pY dual phosphorylation by (dual-mechanism dmERKi). Here, we show eight different ERKi (both catERKi dmERKi) drive turnover ERK2, most abundant ERK isoform, with little no effect on ERK1. Thermal stability assays do not destabilise ERK2 (or ERK1) in vitro, suggesting is cellular consequence binding. observed upon treatment MEKi alone, it binding drives turnover. However, pre-treatment, which blocks and dissociation from MEK1/2, prevents cells poly-ubiquitylation proteasome-dependent pharmacological genetic inhibition Cullin-RING E3 ligases this. Our results suggest ERKi, including current clinical candidates, act as ‘kinase degraders’, driving their major target, ERK2. may be relevant suggestion kinase-independent effects therapeutic use ERKi.

Язык: Английский

Процитировано

11