Hydrogen/Deuterium Exchange Reveals Distinct Agonist/Partial Agonist Receptor Dynamics within Vitamin D Receptor/Retinoid X Receptor Heterodimer

被引：80

作者：

Zhang, Jun ^{[1
]}

Chalmers, Michael J. ^{[1
,2
]}

Stayrook, Keith R. ^{[3
]}

Burris, Lorri L. ^{[3
]}

Garcia-Ordonez, Ruben D. ^{[1
]}

Pascal, Bruce D. ^{[1
,2
]}

Burris, Thomas P. ^{[1
]}

Dodge, Jeffery A. ^{[3
]}

Griffin, Patrick R. ^{[1
,2
]}

机构：

[1] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

[2] Scripps Res Inst, SRMSC, Jupiter, FL 33458 USA

[3] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

STRUCTURE | 2010年 / 18卷 / 10期

基金：

美国国家卫生研究院;

关键词：

MASS-SPECTROMETRY; NUCLEAR RECEPTOR; DEUTERIUM-EXCHANGE; HYDROGEN-EXCHANGE; HORMONE RECEPTORS; D; 25-HYDROXYLASE; ENSEMBLE MODEL; MODULATORS; LIGAND; IDENTIFICATION;

D O I：

10.1016/j.str.2010.07.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Regulation of nuclear receptor (NR) activity is driven by alterations in the conformational dynamics of the receptor upon ligand binding. Previously, we demonstrated that hydrogen/deuterium exchange (HDX) can be applied to determine novel mechanism of action of PPAR gamma ligands and in predicting tissue specificity of selective estrogen receptor modulators. Here, we applied HDX to probe the conformational dynamics of the ligand binding domain (LBD) of the vitamin D receptor (VDR) upon binding its natural ligand 1 alpha,25-dihydroxyvitamin D3 (1,25D3), and two analogs, alfacalcidol and ED-71. Comparison of HDX profiles from ligands in complex with the LBD with full-length receptor bound to its cognate receptor retinoid X receptor (RXR) revealed unique receptor dynamics that could not be inferred from static crystal structures. These results demonstrate that ligands modulate the dynamics of the heterodimer interface as well as provide insight into the role of AF-2 dynamics in the action of VDR partial agonists.

引用

页码：1332 / 1341

页数：10

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