的动态过程 β(2) -上腺素受体激活的激活过程
Rie Nygaard1, Yaozhong Zou, Ron O Dror
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell
|February 5, 2013
概括
G-蛋白结合受体 (GPCRs) 呈现出多种不同的形状. 核磁共振揭示了β-2上腺素受体 (β(2) AR的新状态,显示了它在结合各种配体和蛋白质方面的灵活性.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- G蛋白结合受体 (GPCR) 是关键的细胞表面受体,参与许多生理过程.
- 了解GPCR构造的全谱对于阐明它们的信号机制至关重要.
- β-2上腺素受体 (β(2) AR) 作为研究GPCR动态的模型系统.
研究的目的:
- 使用NMR光谱学来描述β(2) AR的跨膜核心的结构动力学.
- 为了识别除了在静态晶体结构中观察到的之外的功能相关的GPCR构造.
- 为了研究不同的配体 (逆agonist,agonist) 和一个纳米体如何影响β(2) AR形状.
主要方法:
- 利用NMR光谱学,特别是13CH(3) ε-氨酸标签,研究β(2) AR.
- 获得的异核单量子 (HSQC) 光谱的受体在各种连接体结合状态.
- 将NMR数据与现有的晶体结构信息进行比较.
主要成果:
- 鉴定了之前未在晶体结构中观察到的β(2) AR的新型构造状态.
- 在逆agonist和agonist结合β(2) AR制剂中显示出显著的形状异质性.
- 证明,单独的激素结合并不能稳定β(2) AR中的完全活性构造,与罗多普辛不同.
- 显示了连接体结合口袋和G蛋白合表面之间的非刚性构造联系.
结论:
- β(2) AR存在于一个动态的形状组合中,包括未被晶体学捕获的状态.
- 干结合会诱导形状异质性,这表明一个灵活的激活机制.
- 这种形状的灵活性可能是β2AR与多种信号和监管合作伙伴互动的能力的基础.
相关概念视频
01:22Activation and Inactivation of G Proteins
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 affinity and are together...
01:27Adrenergic Receptors (Adrenoceptors): Classification
Adrenergic receptors, or adrenoceptors, respond to the autonomic neurotransmitter noradrenaline and other endogenous catecholamine agonists. They are classified into two main families, α and β, based on their pharmacological response and are further subdivided depending on their location, elicited response, and affinity to specific agonists or antagonists.
α-Adrenoceptors
α-Adrenoceptors are classified into two main subtypes: α1 and α2. The α1 adrenoceptors, which are found on postsynaptic...
α-Adrenoceptors
α-Adrenoceptors are classified into two main subtypes: α1 and α2. The α1 adrenoceptors, which are found on postsynaptic...
01:31Adrenergic Receptors: ɑ Subtype
Adrenoceptors are classified into α and ꞵ classes based on their potencies to catecholamine agonists. α-adrenoceptors show the following order of catecholamine potency:
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...
Adrenaline ≥ Noradrenaline >> Isoprenaline
α-adrenoceptors are further divided into α1 and α2-adrenoceptors.
α1-Adrenoceptors: These receptors are located postsynaptically on the effector organs and cause constriction of smooth muscle mediated by activation of phospholipase C—inositol-1,4,5-trisphosphate...
01:26Adrenergic Receptors: β Subtype
β-adrenoceptors have varied sensitivities towards adrenaline, noradrenaline, and isoprenaline. The order of agonist potency is as follows:
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...
01:31Sympathetic Signaling
Sympathetic signaling, a vital part of the autonomic nervous system, plays a crucial role in mobilizing the body's resources in response to stress or emergencies. It involves the transmission of nerve impulses from sympathetic preganglionic fibers to postganglionic fibers. This results in the release of specific neurotransmitters and activation of adrenergic receptors.
Sympathetic preganglionic fibers release the neurotransmitter acetylcholine (ACh) onto the ganglionic neurons in the...
Sympathetic preganglionic fibers release the neurotransmitter acetylcholine (ACh) onto the ganglionic neurons in the...
01:26Secondary Messengers in Hormone Action
Water-soluble hormones cannot cross the plasma membrane, so they rely on protein receptors that span the membrane to trigger intracellular signaling pathways. These pathways then activate second messengers inside the cell, including cAMP or calcium ions.
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...