为PGC1α招募调RXR调节器
Felix Nawa1, Minh Sai1, Jan Vietor1
1Department of Pharmacy, Ludwig-Maximilians-Universität (LMU) München, 81377 Munich, Germany.
Journal of medicinal chemistry
|September 11, 2024
概括
合成激动剂选择性地将PGC1α招募到核视网体X受体 (RXRs),与内源性配体不同. 这种选择性核心调节器调节为基于RXR的向治疗提供了潜力.
科学领域:
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 核视网体X受体 (RXRs) 通过依赖于连接体的核心压缩剂释放和协同激活剂招募来调节基因表达.
- RXRs多样化的协激活剂结合表明了通过连接体调节选择性激活的潜力.
- 准RXR-coregulator相互作用可能使组织或基因选择性治疗策略成为可能.
研究的目的:
- 为了研究过氧体增殖器激活受体 γ 协同激活剂 1α (PGC1α) 通过合成激动剂对RXR的选择性招募.
- 为治疗应用开发能够产生差异性PGC1α相互作用的新型RXR激活剂.
主要方法:
- 鉴定一种强烈诱导PGC1α与RXR结合的合成激动剂.
- 相关RXR激动剂的结构导向设计和合成.
- 在无细胞和细胞测定中评估PGC1α招募.
主要成果:
- 一种合成激动剂,与9-cis视网酸不同,显著增强了PGC1α与RXR的结合.
- 结构相关的激动剂表现出促进PGC1α招募的不同能力.
- 选择性调节RXR-PGC1α相互作用在体外和细胞环境中都被证明.
结论:
- 通过分子剂,可以实现对RXR的合体诱导的选择性同调节器招募.
- 准RXR-PGC1α相互作用为开发新疗法提供了一个有希望的途径.
- 这种方法可以通过利用RXR通路选择性来开发新的治疗策略.
更多相关视频
07:16Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
13.6K
09:03Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
Published on: March 10, 2020
12.2K
相关概念视频
GPCRs Regulate Adenylyl Cylase Activity
5.3K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.3K
GPCR Desensitization
5.9K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
5.9K
G-Protein Gated Ion Channels
4.5K
GPCRs are primarily responsible for our sense of smell, taste, and vision. The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
Sensory...
4.5K
Activation and Inactivation of G Proteins
6.8K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.8K
Transducer Mechanism: G Protein–Coupled Receptors
1.9K
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
GPCRs are also called heptahelical,...
1.9K
G Protein-coupled Receptors
11.5K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
11.5K
