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相关概念视频

GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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 cells.
Two...
Drug-Receptor Interactions01:29

Drug-Receptor Interactions

Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue.
Drug Distribution: Plasma Protein Binding01:29

Drug Distribution: Plasma Protein Binding

Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Drug-Receptor Interaction: Antagonist01:28

Drug-Receptor Interaction: Antagonist

An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
Antagonists can be classified as competitive or noncompetitive based on their...
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...

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相关实验视频

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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

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通过PPARalpha进行对抗剂介导的核共抑制剂的招募的结构基础.

H Eric Xu1, Thomas B Stanley, Valerie G Montana

  • 1Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. ex11957@gsk.com

Nature
|February 15, 2002
PubMed
概括

核受体通过共抑制剂抑制基因转录. 这项研究揭示了核受体-共抑制体综合体的晶体结构,阐明了基因抑制的保存机制.

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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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科学领域:

  • 分子生物学分子生物学
  • 结构生物学 结构生物学
  • 生物化学 生物化学

背景情况:

  • 核受体对基因转录的抑制涉及联合抑制蛋白质 (例如,SMRT,N-CoR),这些蛋白质会招募基因组脱乙酶.
  • 功能障碍的核受体-共抑制剂相互作用与急性促细胞白血病和甲状腺激素抵抗综合征等疾病有关.
  • 同抑制剂与核受体的结合发生在未结合状态下,可以通过对抗剂来增强.

研究的目的:

  • 确定三元复合体的晶体结构,其中包括氧酶增殖器激活的受体-α连接体结合域,抗体GW6471和SMRT联合抑制器动机.
  • 阐明联合抑制剂结合的结构基础及其在抑制核受体活性中的作用.

主要方法:

  • 进行X射线晶体学以确定三元复杂结构.
  • 生物化学分析.生物化学分析.
  • 基于结构的突变发生.

主要成果:

  • 晶体结构显示了PPAR-alpha LBD,GW6471的三元复合体,以及一个SMRT联合抑制器动机.
  • 联合抑制器图案形成了一个三转的α螺旋,阻碍核受体的碳氧终端激活螺旋 (AF-2) 采用活性构造.
  • 反对者GW6471通过阻止AF-2螺旋回位,进一步稳定了这种压制性构造.

结论:

  • 与对手结合的核受体-共抑制体复合体采用一种形状,可以积极抑制转录.
  • 观察到的联合抑制剂结合模式在不同的核受体中高度保留.
  • 这种结构性洞察力为理解和潜在地针对核受体介导的基因调节提供了基础.