疾病突变的结构基础以及人类SLC2A9载体对基质的识别
Nitesh Kumar Khandelwal1, Meghna Gupta1, Paras Kumar1
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143.
概括
酸盐对于排毒活性氧物种至关重要,在脏中由SLC2A9运输. 新的冷EM结构揭示了它的机制,有助于发现治疗高尿血和痛风的药物.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 尿酸盐是人体血中的主要抗氧化剂,对于排毒活性氧物种至关重要.
- 不调节的尿酸水平,特别是高度 (超尿血),与痛风和结石有关.
- 溶解物载体家族2的9个成员 (SLC2A9) 蛋白质是主要的载体,负责酸盐在脏附近管道中的再吸收.
研究的目的:
- 阐明由SLC2A9.9.介导的尿酸运输的分子基础.
- 了解尿酸选择性和输送背后的结构机制.
- 为了研究与疾病相关的突变在SLC2A9功能中的作用.
主要方法:
- 确定了人体SLC2A9在其和酸盐结合形式的冷电子显微镜 (cryo-EM) 结构.
- 实现分别为3.3 Å和4.1 Å的阿波和酸盐结合结构的分辨率.
- 模拟了面向外的构造,基于确定面向内的结构来分析运输机制.
主要成果:
- 这两种冷-EM结构都显示了SLC2A9在向内开放的形状.
- 对结构的分析阐明了尿酸盐选择性的分子基础.
- 致病突变的确定的位置表明它们对SLC2A9功能的影响.
结论:
- 确定的结构为SLC2A9介导的酸盐运输的交替访问机制提供了前所未有的洞察力.
- 了解尿酸运输的结构基础和突变的影响对于开发向疗法至关重要.
- 这些发现为基于结构的药物发现奠定了基础,以管理高尿血和痛风.
相关概念视频
01:44The Significance of Membrane Transport
21.9K
The transport of solutes across the cell membrane is essential for metabolic processes, like maintaining cell size and volume, generating the action potential, exchanging nutrients and gases, etc. Membrane transport can be either passive or active. It can be simple diffusion, facilitated, or mediated transport aided by transport proteins such as transporters and channels.
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
21.9K
01:27Glucose Transporters
22.4K
Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
22.4K
01:31Translation
141.4K
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
141.4K
01:20Mismatch Repair
4.7K
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
4.7K
01:31Membrane Transporters
10.2K
Transporters are essential membrane transport proteins with functions related to cell nutrition, homeostasis, communication, etc. Approximately 7% of all genes in the human genome code for transporters or transporter-related proteins.
Transporters are mainly composed of alpha-helices, built from bundles of ten or more helices traversing the plasma membrane. The solute-binding sites are located midway, where some of the helices are broken or distorted, making space for the binding site through...
Transporters are mainly composed of alpha-helices, built from bundles of ten or more helices traversing the plasma membrane. The solute-binding sites are located midway, where some of the helices are broken or distorted, making space for the binding site through...
10.2K
01:27ABC Transporters: Importer
2.7K
ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
2.7K