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PMID: 20947021 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Hydrogen/deuterium exchange reveals distinct agonist/partial agonist receptor dynamics within vitamin D receptor/retinoid X receptor heterodimer.

Structure (London, England : 1993) ·Vol. 18 ·No. 10 ·2010-10-13 ·Pages 1332-41

Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Garcia-Ordonez RD, Pascal BD, Burris TP, Dodge JA, Griffin PR

Abstract

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 PPARγ 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 1α,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.

MeSH Terms
Amino Acid Sequence Binding, Competitive Calcitriol/agonists,analogs & derivatives,chemistry,metabolism,pharmacology Crystallography, X-Ray Deuterium/chemistry,metabolism Deuterium Exchange Measurement/methods HEK293 Cells Humans Hydrogen/chemistry,metabolism Hydroxycholecalciferols/agonists,chemistry,metabolism Kinetics Luciferases/genetics,metabolism Mass Spectrometry Models, Molecular Molecular Sequence Data Protein Conformation Protein Multimerization Receptors, Calcitriol/agonists,chemistry,metabolism Retinoid X Receptors/agonists,chemistry,metabolism Transcriptional Activation/drug effects Transfection Vitamin D/analogs & derivatives
Chemicals
Hydroxycholecalciferols Receptors, Calcitriol Retinoid X Receptors Vitamin D Hydrogen Deuterium Luciferases Calcitriol eldecalcitol alfacalcidol
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Zhang Jun
Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
Chalmers Michael J
Stayrook Keith R
Burris Lorri L
Garcia-Ordonez Ruben D
Pascal Bruce D
Burris Thomas P
Dodge Jeffery A
Griffin Patrick R
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
1878-4186
DOI
10.1016/j.str.2010.07.007
Published
2010-10-13
Pages
1332-41
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC2956612
Subset
IM
Grants
NIMH NIH HHS · U54 MH084512 · United States
NIMH NIH HHS · U54-MH074404 · United States
NIDDK NIH HHS · R01 DK080201-05 · United States
NIDDK NIH HHS · R01 DK080201 · United States
NIGMS NIH HHS · R01 GM084041 · United States
NIMH NIH HHS · U54 MH074404 · United States
NCRR NIH HHS · S10 RR027270 · United States
NIGMS NIH HHS · R01-GM084041 · United States
Corrections
CommentIn
PMID: 20947009
External Links
PubMed source DOI: 10.1016/j.str.2010.07.007 PMC Full Text View journal details
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