PMID- 24187139
OWN - NLM
STAT- MEDLINE
DCOM- 20140408
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 2
DP  - 2014 Jan 10
TI  - Defining the communication between agonist and coactivator binding in the 
      retinoid X receptor alpha ligand binding domain.
PG  - 814-26
LID - 10.1074/jbc.M113.476861 [doi]
AB  - Retinoid X receptors (RXRs) are obligate partners for several other nuclear 
      receptors, and they play a key role in several signaling processes. Despite being 
      a promiscuous heterodimer partner, this nuclear receptor is a target of 
      therapeutic intervention through activation using selective RXR agonists 
      (rexinoids). Agonist binding to RXR initiates a large conformational change in 
      the receptor that allows for coactivator recruitment to its surface and enhanced 
      transcription. Here we reveal the structural and dynamical changes produced when 
      a coactivator peptide binds to the human RXRalpha ligand binding domain containing 
      two clinically relevant rexinoids, Targretin and 9-cis-UAB30. Our results show 
      that the structural changes are very similar for each rexinoid and similar to 
      those for the pan-agonist 9-cis-retinoic acid. The four structural changes 
      involve key residues on helix 3, helix 4, and helix 11 that move from a 
      solvent-exposed environment to one that interacts extensively with helix 12. 
      Hydrogen-deuterium exchange mass spectrometry reveals that the dynamics of 
      helices 3, 11, and 12 are significantly decreased when the two rexinoids are 
      bound to the receptor. When the pan-agonist 9-cis-retinoic acid is bound to the 
      receptor, only the dynamics of helices 3 and 11 are reduced. The four structural 
      changes are conserved in all x-ray structures of the RXR ligand-binding domain in 
      the presence of agonist and coactivator peptide. They serve as hallmarks for how 
      RXR changes conformation and dynamics in the presence of agonist and coactivator 
      to initiate signaling.
FAU - Boerma, Leeann J
AU  - Boerma LJ
AD  - From the Departments of Biochemistry and Molecular Genetics.
FAU - Xia, Gang
AU  - Xia G
FAU - Qui, Cheng
AU  - Qui C
FAU - Cox, Bryan D
AU  - Cox BD
FAU - Chalmers, Michael J
AU  - Chalmers MJ
FAU - Smith, Craig D
AU  - Smith CD
FAU - Lobo-Ruppert, Susan
AU  - Lobo-Ruppert S
FAU - Griffin, Patrick R
AU  - Griffin PR
FAU - Muccio, Donald D
AU  - Muccio DD
FAU - Renfrow, Matthew B
AU  - Renfrow MB
LA  - eng
GR  - 5 P50 CA089019/CA/NCI NIH HHS/United States
GR  - RR17261/RR/NCRR NIH HHS/United States
GR  - P50 CA089019/CA/NCI NIH HHS/United States
GR  - 2 P50 CA089019/CA/NCI NIH HHS/United States
GR  - S10 RR017261/RR/NCRR NIH HHS/United States
GR  - R01 GM084041/GM/NIGMS NIH HHS/United States
GR  - S10 RR027270/RR/NCRR NIH HHS/United States
GR  - P30 DK079626/DK/NIDDK NIH HHS/United States
GR  - P30 CA013148/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131101
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Fatty Acids, Unsaturated)
RN  - 0 (Ligands)
RN  - 0 (Naphthalenes)
RN  - 0 (Nuclear Receptor Coactivator 2)
RN  - 0 (Retinoid X Receptor alpha)
RN  - 0 (Tetrahydronaphthalenes)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 5688UTC01R (Tretinoin)
RN  - A61RXM4375 (Bexarotene)
RN  - PFP09575EX (UAB 30)
SB  - IM
MH  - Alitretinoin
MH  - Amino Acid Sequence
MH  - Bexarotene
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Fatty Acids, Unsaturated/chemistry/*metabolism
MH  - Humans
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Molecular Structure
MH  - Naphthalenes/chemistry/*metabolism
MH  - Nuclear Receptor Coactivator 2/chemistry/*metabolism
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Multimerization
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Retinoid X Receptor alpha/chemistry/*metabolism
MH  - Tetrahydronaphthalenes/chemistry/*metabolism
MH  - Tretinoin/chemistry/metabolism
PMC - PMC3887207
OTO - NOTNLM
OT  - 9-cis-UAB30
OT  - Agonists
OT  - Nuclear Receptors
OT  - Protein Dynamics
OT  - RXR Receptor
OT  - Retinoid
OT  - Structural Biology
OT  - Targretin
OT  - X-ray Crystallography
EDAT- 2013/11/05 06:00
MHDA- 2014/04/09 06:00
PMCR- 2015/01/10
CRDT- 2013/11/05 06:00
PHST- 2013/11/05 06:00 [entrez]
PHST- 2013/11/05 06:00 [pubmed]
PHST- 2014/04/09 06:00 [medline]
PHST- 2015/01/10 00:00 [pmc-release]
AID - S0021-9258(20)41554-6 [pii]
AID - M113.476861 [pii]
AID - 10.1074/jbc.M113.476861 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Jan 10;289(2):814-26. doi: 10.1074/jbc.M113.476861. Epub 2013 
      Nov 1.