在原生脂质中,全长整合素αIIbβ3的冷EM结构
Brian D Adair1,2, Jian-Ping Xiong1,2, Mark Yeager3,4,5
1Leukocyte Biology and Inflammation Laboratory, Structural Biology Program, Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA.
Nature communications
|July 13, 2023
概括
血小板整合素αIIbβ3采用一个曲的无活性状态. 冷-EM结构显示,eptifibatide的结合会导致显著的形状变化,这可能解释血静受损,并指导更安全的药物开发.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 细胞生物学 细胞生物学
背景情况:
- 血小板整合素αIIbβ3调解了血栓形成和血液静止.
- αIIbβ3的激活包括形状变化和双向信号.
- 目前的抗αIIbβ3药物可能会损害静血功能.
研究的目的:
- 为了确定全长αIIbβ3.3.的近原子分辨率的冷EM结构.
- 阐明eptifibatide的αIIbβ3激活和抑制的结构基础.
主要方法:
- 全长度αIIbβ3.3.的冷电子显微镜 (冷-EM) 的
- 在原生细胞膜纳米颗粒中对Apo和eptifibatide结合状态的分析.
主要成果:
- 阿波整合蛋白采用一个曲的不活跃状态,有分离的跨膜螺旋.
- 在apo状态下,可以进入带结合部位,这挑战了先前的模型.
- 提巴提德的结合会导致αIIbβ3.3的形状发生剧烈的变化.
结论:
- 对αIIbβ3.3的无活性和药物结合状态的结构洞察.
- 这些发现挑战了现有的带结合部位可访问性模型.
- 结果可能会为开发更安全的抗血小板治疗药物提供信息.
相关概念视频
Integrins
4.0K
Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
4.0K
Activation of Integrins
3.5K
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
3.5K
Intracellular Signaling Affects Focal Adhesions
2.7K
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
2.7K
Assembly of the Lipid Bilayer in the ER
3.2K
Biological membranes are more than just a barrier separating cell cytoplasm from the outside environment. They are highly dynamic and help maintain the integrity and physiological stability of the cells as well as membrane-bound organelles. Membranes also play vital roles in cell-to-cell and intracellular communication.
A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between...
A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between...
3.2K


