Differential hydrogen/deuterium exchange mass spectrometry analysis of protein-ligand interactions.
Differential hydrogen/deuterium exchange mass spectrometry analysis of protein-ligand interactions.
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DOI：
10.1586/epr.10.109
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发表时间：
2011-02
影响因子：
3.4
通讯作者：
Griffin PR
中科院分区：
文献类型：
--
作者：
Chalmers MJ;Busby SA;Pascal BD;West GM;Griffin PR
配体激活受体的功能调节由配体结合后蛋白质构象动力学的改变驱动。差分氢/氘交换（HDX）与质谱联用已成为一种快速，灵敏的方法来表征蛋白质的构象动力学扰动配体结合。虽然这种技术对检测配体相互作用和受体动力学改变敏感，但它也可以为配体调控提供重要的机制见解。例如，HDX已用于确定核受体过氧化物酶体增殖物激活受体-γ的配体激活的新机制，对两种雌激素受体同种型的配体结合口袋内的配体结合模式进行详细分析，提供对选择性的洞察，并帮助分类不同类型的雌激素受体α配体通过将其药理学与其与受体相互作用的方式相关联，仅基于受体HDX特征的分层聚类。除了小分子-受体相互作用之外，该技术还被应用于研究蛋白质-蛋白质复合物，例如绘制抗体-抗原相互作用。在这篇文章中，我们总结了差分HDX方法的现状和未来的展望。我们总结了蛋白质-配体相互作用的HDX分析如何对生物学和药物发现产生影响。
Functional regulation of ligand-activated receptors is driven by alterations in the conformational dynamics of the protein upon ligand binding. Differential hydrogen/deuterium exchange (HDX) coupled with mass spectrometry has emerged as a rapid and sensitive approach for characterization of perturbations in conformational dynamics of proteins following ligand binding. While this technique is sensitive to detecting ligand interactions and alterations in receptor dynamics, it also can provide important mechanistic insights into ligand regulation. For example, HDX has been used to determine a novel mechanism of ligand activation of the nuclear receptor peroxisome proliferator activated receptor-γ, perform detailed analyses of binding modes of ligands within the ligand-binding pocket of two estrogen receptor isoforms, providing insight into selectivity, and helped classify different types of estrogen receptor-α ligands by correlating their pharmacology with the way they interact with the receptor based solely on hierarchical clustering of receptor HDX signatures. Beyond small-molecule–receptor interactions, this technique has also been applied to study protein–protein complexes, such as mapping antibody–antigen interactions. In this article, we summarize the current state of the differential HDX approaches and the future outlook. We summarize how HDX analysis of protein–ligand interactions has had an impact on biology and drug discovery.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.4
作者：
Chik, JK;Graaf, JLV;Schriemer, DC
通讯作者：
Schriemer, DC
影响因子：
7.4
作者：
Charlebois, JP;Patrie, SM;Kelleher, NL
通讯作者：
Kelleher, NL
影响因子：
8
作者：
Burns-Hamuro, LL;Hamuro, Y;Woods, VL
通讯作者：
Woods, VL