更新于：2024-11-01

STK39

更新于：2024-11-01

基本信息

别名

DCHT、serine threonine kinase 39、serine/threonine kinase 39

+ [6]

简介

May act as a mediator of stress-activated signals. Mediates the inhibition of SLC4A4, SLC26A6 as well as CFTR activities by the WNK scaffolds, probably through phosphorylation. Phosphorylates RELT.

关联

项与 STK39 相关的药物

Rafoxanide

靶点

OSR1 x STK39

作用机制

OSR1 inhibitors [+1]

在研机构

University of Birmingham

原研机构

University of Birmingham

在研适应症

高血压

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

Stock 1S-14279

靶点

STK39

作用机制

STK39抑制剂

在研机构

Tokyo Medical & Dental University

原研机构

Tokyo Medical & Dental University

在研适应症

高血压

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

closantel

氯生太尔

靶点

OSR1 x STK39

作用机制

OSR1 inhibitors [+1]

在研机构

University of Birmingham

原研机构

University of Birmingham

在研适应症

高血压

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 STK39 相关的临床结果

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100 项与 STK39 相关的转化医学

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0 项与 STK39 相关的专利（医药）

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1,726

项与 STK39 相关的文献（医药）

2024-11-01·American Journal of Physiology-Renal Physiology

Macrophage SPAK deletion limits a low potassium-induced kidney inflammatory program

Article

作者: Zhang, Yahua ; Wu, Aihua ; Terker, Andrew S. ; Harris, Raymond C. ; Delpire, Eric ; Bock, Fabian ; Arroyo, Juan Pablo ; Zhang, Ming-Zhi

Global Ste20p-related proline alanine-rich kinase (SPAK) deletion protects against harmful kidney effects of dietary K+ deficiency. Exposure to low K+ conditions increases SPAK phosphorylation and induces SPAK to adopt a punctate staining pattern. Macrophage-specific deletion of SPAK confers protection to low K+-induced kidney injury in vivo. Macrophage-expressed SPAK plays a key role in the development of kidney injury in response to a low K+ diet.

2024-10-24·Journal of Bacteriology

Molecular dissection of the chromosome partitioning protein RocS and regulation by phosphorylation

Article

作者: Ducret, Adrien ; Demuysere, Margaux ; Grangeasse, Christophe

ABSTRACT Chromosome segregation in bacteria is a critical process ensuring that each daughter cell receives an accurate copy of the genetic material during cell division. Active segregation factors, such as the ParABS system or SMC complexes, are usually essential for this process, but they are surprisingly dispensable in Streptococcus pneumoniae . Rather, chromosome segregation in S. pneumoniae relies on the protein Regulator of Chromosome Segregation (RocS), although the molecular mechanisms involved remain elusive. By combining genetics, in vivo imaging, and biochemical approaches, we dissected the molecular features of RocS involved in chromosome segregation. We investigated the respective functions of the three RocS domains, specifically the C-terminal amphipathic helix (AH), the N-terminal DNA-binding domain (DBD), and the coiled-coil domain (CCD) separating the AH and the DBD. Notably, we found that a single AH is not sufficient for membrane binding and that RocS requires prior oligomerization to interact with the membrane. We further demonstrated that this self-interaction was driven by the N-terminal part of the CCD. On the other hand, we revealed that the C-terminal part of the CCD corresponds to a domain of unknown function (DUF 536) and is defined by three conserved glutamines, which play a crucial role in RocS-mediated chromosome segregation. Finally, we showed that the DBD is phosphorylated by the unique serine-threonine kinase of S. pneumoniae StkP and that mimicking this phosphorylation abrogated RocS binding to DNA. Overall, this study offers new insights into chromosome segregation in Streptococci and paves the way for a deeper understanding of RocS-like proteins in other bacteria. IMPORTANCE Bacteria have evolved a variety of mechanisms to properly segregate their genetic material during cell division. In this study, we performed a molecular dissection of the chromosome partitioning protein Regulator of Chromosome Segregation (RocS), a pillar element of chromosome segregation in S. pneumoniae that is also generally conserved in the Streptococcaceae family. Our systematic investigation sheds light on the molecular features required for successful pneumococcal chromosome segregation and the regulation of RocS by phosphorylation. In addition, our study also revealed that RocS shares functional domains with the Par protein, involved in an atypical plasmid segregation system. Therefore, we expect that our findings may serve to extend our understanding of RocS and RocS-like proteins while broadening the repertoire of partitioning systems used in bacteria.

2024-10-01·Bioorganic Chemistry

7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions

Article

作者: Bassani, Davide ; Moro, Stefano ; Salmaso, Veronica ; Trevisan, Letizia ; Martinez-Gonzalez, Loreto ; Federico, Stephanie ; Prencipe, Filippo ; Grieco, Ilenia ; Da Ros, Tatiana ; Spalluto, Giampiero ; Cescon, Eleonora ; Martinez, Ana

CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC₅₀s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC₅₀ < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.