合理的进化改变雌激素受体α的连接物偏好
Roy Eerlings1,2,3, Purvi Gupta4, Xiao Yin Lee1
1Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Protein science : a publication of the Protein Society
|March 21, 2024
概括
研究人员设计了一种新的雌激素受体变体,TERRA,被他莫西芬激活而不是雌激素. 这一进步通过克服细胞过程中的雌激素干扰来增强合成生物学工具.
科学领域:
- 合成生物学 合成生物学
- 分子生物学分子生物学
- 蛋白质工程是指蛋白质工程.
背景情况:
- 雌激素受体α是合成生物学中控制基因组编辑工具的关键组成部分.
- 自然雌激素配体破坏细胞功能,限制受体的合成生物学应用.
- 修改配体偏好对于扩大雌激素受体的效用至关重要.
研究的目的:
- 为增强合成生物学应用设计一种雌激素受体变异体,具有改变的连接体特异性.
- 开发一个平台来修改类固醇受体连接体偏好和药物耐药性概况.
主要方法:
- 结合了合理的蛋白质设计,多部位定向突变发生和Saccharomyces cerevisiae的定向进化.
- 选了带有改变连接体响应性的变体.
- 在哺乳动物细胞和小鼠中验证的他莫西芬激活变体 (TERRA).
主要成果:
- 开发了TERRA,一种雌激素受体变体不对雌激素有反应,但被tamoxifen激活.
- 在哺乳动物细胞和体内模型 (老鼠) 中证实了TERRA对他莫西芬的偏好.
- 当与Cre复合酶融合时,TERRA保持了功能,扩大了其在哺乳动物合成生物学中的应用.
结论:
- 开发的平台使得对类固醇受体的配体偏好的工程成为可能,提供了一种多功能合成生物学工具.
- TERRA为基因组编辑提供了一个可以诱导他莫西芬的系统,克服了基于雌激素的系统的局限性.
- 该方法可用于在类固醇受体向治疗中对药物耐药性景观进行分析.
相关概念视频
01:31Transducer Mechanism: Nuclear Receptors
1.3K
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:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.3K
01:29The Two-State Receptor Model
1.9K
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...
The binding affinity of a drug determines its interaction with...
1.9K
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
02:40Ligand Binding Sites
12.8K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.8K
01:12GPCR Desensitization
6.0K
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...
6.0K