PMID- 11149488
OWN - NLM
STAT- MEDLINE
DCOM- 20010301
LR  - 20131121
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 16
IP  - 1
DP  - 2001 Jan
TI  - The unique tryptophan residue of the vitamin D receptor is critical for ligand 
      binding and transcriptional activation.
PG  - 39-45
AB  - The human vitamin D receptor (hVDR) is a member of the nuclear receptor 
      superfamily of transcriptional regulators. Here we show that tryptophan 286 of 
      the hVDR is critical for ligand binding and transactivation of 
      1,25-dihydroxyvitamin D3 [1,25(OH)2D3] target genes. Two mutants of the hVDR were 
      produced, W286A and W286F, in which the tryptophan was replaced with an alanine 
      or a phenylalanine, respectively. The W286A mutant did not bind 1,25(OH)2D3, 
      interact with steroid receptor coactivator 1 (SRC-1) in vitro, or activate 
      transcription. Moreover, the W286A receptor did not heterodimerize in a 
      ligand-dependent manner with the human retinoid X receptor alpha (hRXRalpha). 
      Although the W286F receptor heterodimerized with hRXRalpha, interacted with 
      SRC-1, and bound 1,25(OH)2D3, its capacity to transactivate was attenuated 
      severely. Thus, tryptophan 286 of hVDR plays an important role in specific 
      1,25(OH)2D3 ligand interaction and subsequently in hVDR/RXR interaction, SRC-1 
      binding, and ligand-dependent transactivation of 1,25(OH)2D3 target genes. These 
      results identify the first amino acid that is absolutely required for ligand 
      binding in the VDR and further define the structure-function relationship of 
      1,25(OH)2D3 interaction with its receptor.
FAU - Solomon, C
AU  - Solomon C
AD  - Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, 
      Quebec, Canada.
FAU - Macoritto, M
AU  - Macoritto M
FAU - Gao, X L
AU  - Gao XL
FAU - White, J H
AU  - White JH
FAU - Kremer, R
AU  - Kremer R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Ligands)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - 1406-16-2 (Vitamin D)
RN  - 66772-14-3 (1,25-dihydroxyvitamin D)
RN  - 8DUH1N11BX (Tryptophan)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.3.1.48 (NCOA1 protein, human)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
SB  - IM
MH  - Amino Acid Substitution/genetics
MH  - Animals
MH  - Blotting, Western
MH  - COS Cells
MH  - Dimerization
MH  - Histone Acetyltransferases
MH  - Humans
MH  - Ligands
MH  - Mutation/genetics
MH  - Nuclear Receptor Coactivator 1
MH  - Protein Binding
MH  - Receptors, Calcitriol/*chemistry/genetics/*metabolism
MH  - Receptors, Retinoic Acid/metabolism
MH  - Recombinant Fusion Proteins/chemistry/metabolism
MH  - Retinoid X Receptors
MH  - Transcription Factors/metabolism
MH  - *Transcriptional Activation/drug effects
MH  - Transfection
MH  - Tryptophan/genetics/*metabolism
MH  - Vitamin D/*analogs & derivatives/metabolism
EDAT- 2001/01/10 11:00
MHDA- 2001/03/07 10:01
CRDT- 2001/01/10 11:00
PHST- 2001/01/10 11:00 [pubmed]
PHST- 2001/03/07 10:01 [medline]
PHST- 2001/01/10 11:00 [entrez]
AID - 10.1359/jbmr.2001.16.1.39 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2001 Jan;16(1):39-45. doi: 10.1359/jbmr.2001.16.1.39.