PMID- 29030554
OWN - NLM
STAT- MEDLINE
DCOM- 20180222
LR  - 20181113
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Oct 13
TI  - HDX reveals the conformational dynamics of DNA sequence specific VDR co-activator 
      interactions.
PG  - 923
LID - 10.1038/s41467-017-00978-7 [doi]
LID - 923
AB  - The vitamin D receptor/retinoid X receptor-alpha heterodimer (VDRRXRalpha) regulates bone 
      mineralization via transcriptional control of osteocalcin (BGLAP) gene and is the 
      receptor for 1alpha,25-dihydroxyvitamin D(3) (1,25D3). However, supra-physiological 
      levels of 1,25D3 activates the calcium-regulating gene TRPV6 leading to 
      hypercalcemia. An approach to attenuate this adverse effect is to develop 
      selective VDR modulators (VDRMs) that differentially activate BGLAP but not 
      TRPV6. Here we present structural insight for the action of a VDRM compared with 
      agonists by employing hydrogen/deuterium exchange. Agonist binding directs 
      crosstalk between co-receptors upon DNA binding, stabilizing the activation 
      function 2 (AF2) surfaces of both receptors driving steroid receptor 
      co-activator-1 (SRC1) interaction. In contrast, AF2 of VDR within VDRM:BGLAP 
      bound heterodimer is more vulnerable for large stabilization upon SRC1 
      interaction compared with VDRM:TRPV6 bound heterodimer. These results reveal that 
      the combination of ligand structure and DNA sequence tailor the transcriptional 
      activity of VDR toward specific target genes.The vitamin D receptor/retinoid X 
      receptor-alpha heterodimer (VDRRXRalpha) regulates bone mineralization. Here the authors 
      employ hydrogen/deuterium exchange (HDX) mass spectrometry to study the 
      conformational dynamics of VDRRXRalpha and give mechanistic insights into how VDRRXRalpha 
      controls the transcriptional activity of specific genes.
FAU - Zheng, Jie
AU  - Zheng J
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 
      33458, USA.
FAU - Chang, Mi Ra
AU  - Chang MR
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 
      33458, USA.
FAU - Stites, Ryan E
AU  - Stites RE
AD  - Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
FAU - Wang, Yong
AU  - Wang Y
AD  - Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
FAU - Bruning, John B
AU  - Bruning JB
AD  - The University of Adelaide, Institute for Photonics & Advanced Sensing (IPAS), 
      School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, 
      Australia.
FAU - Pascal, Bruce D
AU  - Pascal BD
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 
      33458, USA.
FAU - Novick, Scott J
AU  - Novick SJ
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 
      33458, USA.
FAU - Garcia-Ordonez, Ruben D
AU  - Garcia-Ordonez RD
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 
      33458, USA.
FAU - Stayrook, Keith R
AU  - Stayrook KR
AD  - Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
FAU - Chalmers, Michael J
AU  - Chalmers MJ
AD  - Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
FAU - Dodge, Jeffrey A
AU  - Dodge JA
AD  - Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
FAU - Griffin, Patrick R
AU  - Griffin PR
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 
      33458, USA. pgriffin@scripps.edu.
LA  - eng
GR  - S10 RR027270/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20171013
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Ligands)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (dihydroxy-vitamin D3)
RN  - 104982-03-8 (Osteocalcin)
RN  - 1406-16-2 (Vitamin D)
RN  - 7YNJ3PO35Z (Hydrogen)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - DNA/*chemistry/genetics/metabolism
MH  - Deuterium Exchange Measurement
MH  - Dimerization
MH  - Humans
MH  - Hydrogen
MH  - Ligands
MH  - Mass Spectrometry
MH  - Osteocalcin/genetics/metabolism
MH  - Protein Binding
MH  - Receptors, Calcitriol/*chemistry/genetics/*metabolism
MH  - Retinoid X Receptors/chemistry/genetics/metabolism
MH  - Vitamin D/analogs & derivatives/metabolism
PMC - PMC5640644
COIS- The authors declare no competing financial interests.
EDAT- 2017/10/17 06:00
MHDA- 2018/02/23 06:00
PMCR- 2017/10/13
CRDT- 2017/10/15 06:00
PHST- 2017/03/14 00:00 [received]
PHST- 2017/08/09 00:00 [accepted]
PHST- 2017/10/15 06:00 [entrez]
PHST- 2017/10/17 06:00 [pubmed]
PHST- 2018/02/23 06:00 [medline]
PHST- 2017/10/13 00:00 [pmc-release]
AID - 10.1038/s41467-017-00978-7 [pii]
AID - 978 [pii]
AID - 10.1038/s41467-017-00978-7 [doi]
PST - epublish
SO  - Nat Commun. 2017 Oct 13;8(1):923. doi: 10.1038/s41467-017-00978-7.