Modulation of allostery of pyruvate kinase by shifting of an ensemble of microstates.
Modulation of allostery of pyruvate kinase by shifting of an ensemble of microstates.
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DOI：
10.1111/j.1745-7270.2008.00445.x
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发表时间：
2008-07
影响因子：
3.7
通讯作者：
Lee JC
中科院分区：
文献类型：
--
作者：
Lee JC
自四十多年前变构概念被提出以来，对变构中结构-功能关系的研究取得了很大进展。然而，仍有一些问题尚未解决。在这篇综述中，我们采用哺乳动物丙酮酸激酶（PK）作为模型系统来了解蛋白质动力学在调节协同性中的作用。PK具有TIM (α/β)8桶结构基序。PK是解决这一常见（α/β）8结构基序调控机制基本问题的理想系统。解释配体与酶相互作用的所有溶液热力学和动力学数据的最简单模型涉及两种构象状态：非活性ET和活性ER。这些构象状态用畴运动来表示。进一步的研究为配体结合对结构元素动力学的差异影响提供了第一个证据，而不是主要的次要结构变化。这些数据与我们的模型一致，即PK的变构调节是扰动状态集合分布的结果，其中非活性ET和活性ER代表两个极端末端状态。序列差异和配体可以调节状态的分布，导致功能的改变。未来的工作包括：定义功能连通残基网络；阐明影响功能的序列差异的化学原理；并探讨突变对二级结构元件稳定性的影响，从而调节变构。
Since the introduction of the concepts of allostery about four decades ago, much advancement has been made in elucidating the structure-function correlation in allostery. However, there are still a number of issues that remain unresolved. In this review we employed mammalian pyruvate kinase (PK) as a model system to understand the role of protein dynamics in modulating cooperativity. PK has a TIM (α/β)8 barrel structural motif. PK is an ideal system to address basic questions regarding regulatory mechanisms about this common (α/β)8 structural motif. The simplest model accounting for all the solution thermodynamic and kinetic data on ligand-enzyme interactions involves two conformational states, inactive ET and active ER. These conformational states are represented by domain movements. Further studies provide the first evidence for a differential effect of ligand binding on the dynamics of the structural elements, not major secondary structural changes. These data are consistent with our model that allosteric regulation of PK is the consequence of perturbation of the distribution of an ensemble of states in which the inactive ET and active ER represent the two extreme end states. Sequence differences and ligands can modulate the distribution of states leading to alterations of functions. The future work includes: defining the network of functionally connected residues; elucidate the chemical principles governing the sequence differences which affect functions; and probe the nature of mutations on the stability of the secondary structural elements which in turn modulate allostery.
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影响因子：
2.9
作者：
Friesen, RHE;Castellani, RJ;Braun, W
通讯作者：
Braun, W
影响因子：
3.8
作者：
Hilser, VJ;Townsend, BD;Freire, E
通讯作者：
Freire, E
DOI：
10.1073/pnas.96.18.10118
发表时间：
1999-08-31
影响因子：
11.1
作者：
Freire, E
通讯作者：
Freire, E
DOI：
10.1073/pnas.95.17.9903
发表时间：
1998-08-18
影响因子：
11.1
作者：
Hilser, VJ;Dowdy, D;Freire, E
通讯作者：
Freire, E
影响因子：
2.9
作者：
LARSEN, TM;LAUGHLIN, LT;REED, GH
通讯作者：
REED, GH