PMID- 17223691
OWN - NLM
STAT- MEDLINE
DCOM- 20070305
LR  - 20240312
IS  - 0006-2960 (Print)
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Linking)
VI  - 46
IP  - 3
DP  - 2007 Jan 23
TI  - Structural and functional characterization of the aryl hydrocarbon receptor 
      ligand binding domain by homology modeling and mutational analysis.
PG  - 696-708
AB  - The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor 
      that is activated by a structurally diverse array of synthetic and natural 
      chemicals, including toxic halogenated aromatic hydrocarbons such as 
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Analysis of the molecular events 
      occurring in the AhR ligand binding and activation processes requires structural 
      information on the AhR Per-Arnt-Sim (PAS) B-containing ligand binding domain, for 
      which no experimentally determined structure has been reported. With the 
      availability of extensive structural information on homologous PAS-containing 
      proteins, a reliable model of the mouse AhR PAS B domain was developed by 
      comparative modeling techniques. The PAS domain structures of the functionally 
      related hypoxia-inducible factor 2alpha (HIF-2alpha) and AhR nuclear translocator 
      (ARNT) proteins, which exhibit the highest degree of sequence identity and 
      similarity with AhR, were chosen to develop a two-template model. To confirm the 
      features of the modeled domain, the effects of point mutations in selected 
      residue positions on both TCDD binding to the AhR and TCDD-dependent 
      transformation and DNA binding were analyzed. Mutagenesis and functional analysis 
      results are consistent with the proposed model and confirm that the cavity 
      modeled in the interior of the domain is indeed involved in ligand binding. 
      Moreover, the physicochemical characteristics of some residues and of their 
      mutants, along with the effects of mutagenesis on TCDD and DNA binding, also 
      suggest some key features that are required for ligand binding and activation of 
      mAhR at a molecular level, thus providing a framework for further studies.
FAU - Pandini, Alessandro
AU  - Pandini A
AD  - Dipartimento di Scienze dell'Ambiente e del Territorio, Universita degli Studi di 
      Milano-Bicocca, Piazza della Scienza, 1, 20126 Milano, Italy.
FAU - Denison, Michael S
AU  - Denison MS
FAU - Song, Yujuan
AU  - Song Y
FAU - Soshilov, Anatoly A
AU  - Soshilov AA
FAU - Bonati, Laura
AU  - Bonati L
LA  - eng
GR  - F32 ES005707/ES/NIEHS NIH HHS/United States
GR  - R01 ES007685-10/ES/NIEHS NIH HHS/United States
GR  - R01 ES007685/ES/NIEHS NIH HHS/United States
GR  - P30 ES005707-159002/ES/NIEHS NIH HHS/United States
GR  - P30 ES005707/ES/NIEHS NIH HHS/United States
GR  - ES07685/ES/NIEHS NIH HHS/United States
GR  - ES05707/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (ARNT protein, human)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Ligands)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Transcription Factors)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism
MH  - Basic Helix-Loop-Helix Transcription Factors
MH  - Binding Sites
MH  - Humans
MH  - Ligands
MH  - Mice
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - *Protein Structure, Tertiary
MH  - Receptors, Aryl Hydrocarbon/*chemistry/*physiology
MH  - Sequence Alignment
MH  - Structural Homology, Protein
MH  - Transcription Factors/metabolism
PMC - PMC2860805
MID - NIHMS193210
EDAT- 2007/01/17 09:00
MHDA- 2007/03/06 09:00
PMCR- 2010/04/28
CRDT- 2007/01/17 09:00
PHST- 2007/01/17 09:00 [pubmed]
PHST- 2007/03/06 09:00 [medline]
PHST- 2007/01/17 09:00 [entrez]
PHST- 2010/04/28 00:00 [pmc-release]
AID - 10.1021/bi061460t [doi]
PST - ppublish
SO  - Biochemistry. 2007 Jan 23;46(3):696-708. doi: 10.1021/bi061460t.