The gating isomerization of neuromuscular acetylcholine receptors
The gating isomerization of neuromuscular acetylcholine receptors
复制标题
DOI：
10.1113/jphysiol.2009.182774
复制
发表时间：
2010-02-15
影响因子：
5.5
通讯作者：
Auerbach, Anthony
中科院分区：
文献类型：
--
作者：
Auerbach, Anthony
乙酰胆碱受体通道是变构蛋白，在对递质和离子电导具有低亲和力和高亲和力的构象之间异构化（“门”）。为了理解亲和力和电导变化的关联机制，了解流经系统的能量的大小、时间和分布是有价值的。了解双配体和无配体的门控平衡常数（E(2) 和 E(0)）是理解 AChR 门控机制以及设计配体和蛋白质以可预测方式运行的基础。在乙酰胆碱激活的成年小鼠神经肌肉受体中，E(2) = 28，E(0) 近似于 6.5 x 10-7。在每个（等效）递质结合位点，乙酰胆碱提供类似于 5.2 kcal mol-1 的能量来激发异构化。部分激动剂胆碱提供类似于 3.3 kcal mol-1 的能量。残基门控能量变化的相对时间由其速率-平衡常数关系的斜率揭示。该参数的图表明能量作为递质结合位点和门区域之间的构象级联传播。尽管门控能量变化在整个蛋白质中广泛存在，但某些残基对扰动特别敏感。讨论了构成门控构象级联的结构事件的几个具体建议。
Acetylcholine receptor-channels are allosteric proteins that isomerize ('gate') between conformations that have a low vs. high affinity for the transmitter and conductance for ions. In order to comprehend the mechanism by which the affinity and conductance changes are linked it is of value to know the magnitude, timing and distribution of energy flowing through the system. Knowing both the di- and unliganded gating equilibrium constants (E(2) and E(0)) is a foundation for understanding the AChR gating mechanism and for engineering both the ligand and the protein to operate in predictable ways. In adult mouse neuromuscular receptors activated by acetylcholine, E(2) = 28 and E(0) approximate to 6.5 x 10-7. At each (equivalent) transmitter binding site acetylcholine provides similar to 5.2 kcal mol-1 to motivate the isomerization. The partial agonist choline provides similar to 3.3 kcal mol-1. The relative time of a residue's gating energy change is revealed by the slope of its rate-equilibrium constant relationship. A map of this parameter suggests that energy propagates as a conformational cascade between the transmitter binding sites and the gate region. Although gating energy changes are widespread throughout the protein, some residues are particularly sensitive to perturbations. Several specific proposals for the structural events that comprise the gating conformational cascade are discussed.