Dai Susie Y, Burris Thomas P, Dodge Jeffrey A, Montrose-Rafizadeh Chahrzad, Wang Yong, Pascal Bruce D, Chalmers Michael J, Griffin Patrick R
Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
Biochemistry. 2009 Oct 13;48(40):9668-76. doi: 10.1021/bi901149t.
Here we present the use of hydrogen-deuterium exchange (HDX) mass spectrometry in analyzing the estrogen receptor beta ligand binding domain (ERbeta LBD) in the absence and presence of a variety of chemical compounds with different binding modes and pharmacological properties. Previously, we reported the use of HDX as a method for predicting the tissue selectivity of ERalpha ligands. HDX profiles of ERalpha LBD in complex with ligand could differentiate compounds of the same chemotype. In contrast, similar analysis of ERbeta LBD showed correlation to the compound chemical structures but little correlation with compound tissue selectivity. The different HDX patterns observed for ERbeta LBD when compared to those for ERalpha LBD bound to the same chemical compounds serve as an indication that ERbeta LBD undergoes a different structural response to the same ligand when compared to ERalpha LBD. The conformational dynamics revealed by HDX for ERbeta LBD together with those for ERalpha LBD shed light on ER ligand interactions and offer new structural insights. The compound-specific perturbations in HDX kinetics observed for each of the two isoforms should aid the development of subtype-selective ER ligands.
在此，我们展示了氢-氘交换（HDX）质谱法在分析雌激素受体β配体结合域（ERβ LBD）时的应用，该分析分别在不存在和存在多种具有不同结合模式和药理特性的化合物的情况下进行。此前，我们报道了使用HDX作为预测ERα配体组织选择性的方法。与配体结合的ERα LBD的HDX图谱能够区分相同化学类型的化合物。相比之下，对ERβ LBD的类似分析显示与化合物化学结构相关，但与化合物组织选择性相关性较小。与结合相同化合物的ERα LBD相比，ERβ LBD观察到的不同HDX模式表明，与ERα LBD相比，ERβ LBD对相同配体的结构响应不同。HDX揭示的ERβ LBD与ERα LBD的构象动力学为ER配体相互作用提供了线索，并提供了新的结构见解。在两种亚型中观察到的HDX动力学中化合物特异性的扰动应有助于亚型选择性ER配体的开发。
