原生AMPA受体复合体的结构和不同的构造状态
Terunaga Nakagawa1, Yifan Cheng, Elizabeth Ramm
1The Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Nature
|February 4, 2005
概括
这项研究揭示了来自老鼠大脑的原生AMPA受体 (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid受体) 的3D结构. 研究结果表明,这些关键的大脑受体存在于各种形状,影响突触传输和神经疾病的理解.
科学领域:
- 神经科学是一个神经科学.
- 结构生物学 结构生物学
- 分子生物学分子生物学
背景情况:
- 离子型谷氨酸受体,包括AMPA受体 (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid受体),对于中枢神经系统中快速激发性突触传播至关重要.
- 这些受体的功能障碍与神经和精神疾病有关,但它们完整的3D结构在很大程度上是未知的.
研究的目的:
- 为了确定从老鼠大脑中净化的原生α-amino-3-hydroxy-5-methyl-4-isoxazole酸受体 (AMPA-Rs) 的三维结构.
- 为了研究构造状态和相关蛋白质在AMPA-R功能中的作用.
主要方法:
- 单粒子电子显微镜被用来解决本地AMPA-Rs.的结构.
- 从大鼠大脑组织中净化AMPA-Rs进行了.
主要成果:
- 原生异构四基AMPA-Rs表现出多样化的构造,主要以其氨基终端域的可变分离为特征.
- 星加津/TARP家族蛋白被共同净化,并对受体复合体的跨膜区域作出贡献.
- 像谷氨酸酸和环亚胺这样的配体显著影响了构造平衡,这表明脱敏和N端域分离之间存在联系.
结论:
- 这项研究首次提供了在各种构造状态下对本源AMPA受体的结构见.
- 这些发现阐明了AMPA-R形态动态的结构基础及其通过配体和相关蛋白质的调制.
- 了解这些结构对于破译突触传输机制和开发神经疾病治疗策略至关重要.
相关概念视频
Cooperative Allosteric Transitions
7.4K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
7.4K
Protein Folding
8.8K
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
8.8K
Assembly of Signaling Complexes
4.7K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
4.7K
Activation and Inactivation of G Proteins
8.9K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
8.9K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
4.6K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
4.6K
The Two-State Receptor Model
3.5K
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...
3.5K


