莱普丁受体的纤维素第III类型受体域中的致病变体:分子动力学模拟和结构分析
Takashi Kato1, Fumiko Matsuzawa2, Nobuhiro Shojima1
1Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Journal of molecular graphics & modelling
|November 28, 2024
概括
与肥胖相关的瘦素受体 (LEPR) 变体可以破坏其3D结构. 分子动力学模拟显示,特定的LEPR纤维素3型域变异破坏了蛋白质的稳定性,影响了对体重调节至关重要的信号通路.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 遗传学 是一个遗传学.
背景情况:
- 莱普受体 (LEPR) 变异与严重肥胖有关.
- 莱普尔的三维结构,特别是其纤维素第III类 (FnIII) 域,对于信号传导至关重要,但仍然不完全理解.
- 很少有研究研究了LEPR变体的结构影响.
研究的目的:
- 为了研究10个误解变体在素受体的FnIII域内对其3D结构和稳定性的影响.
- 阐明与肥胖相关的LEPR变体的致病机制.
主要方法:
- 用分子动力学 (MD) 模拟 (300 ns) 来分析LEPR变体的结构效应.
- 进行了结构分析,包括根平均平方偏差 (RMSD) 计算和折叠核的识别.
- 生物信息学工具被用于损害预测得分.
主要成果:
- 这种C604S变体破坏了二硫化物键,显著增加了RMSD并破坏了FnIII-2和FnIII-3域的稳定.
- 变种P639L,N718S和W646C导致异常的域间曲和旋转,导致不稳定.
- 发现L662S,W664R,H684P和S723F变种破坏了内部域结构的稳定性.
- 影响域间区域的变种显示损害预测得分低于预期.
结论:
- 在LEPR FnIII域中错误的变异可以显著破坏蛋白质结构的稳定.
- 结构性干扰,包括变化的域间刚性和内部域折叠,有助于LEPR功能障碍.
- 这项研究提供了关于LEPR变体相关的肥胖症背后的分子机制的见解.
更多相关视频
15:05Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
8.5K
10:50Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 15, 2010
9.6K
相关概念视频
02:28Leaky Scanning
5.1K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.1K
02:21Globular and Fibrous Proteins
43.4K
Many proteins can be classified into two distinct subtypes - globular or fibrous. These two types differ in their shapes and solubilities.
Globular proteins are also known as spheroproteins and typically are approximately round in shape. They contain a mix of amino acid types and contain differing sequences in their primary structures. Globular proteins have many different functions, such as enzymes, cellular messengers, and molecular transporters. These roles often require the proteins to be...
Globular proteins are also known as spheroproteins and typically are approximately round in shape. They contain a mix of amino acid types and contain differing sequences in their primary structures. Globular proteins have many different functions, such as enzymes, cellular messengers, and molecular transporters. These roles often require the proteins to be...
43.4K