PMID- 11089639
OWN - NLM
STAT- MEDLINE
DCOM- 20010607
LR  - 20131121
IS  - 0739-1102 (Print)
IS  - 0739-1102 (Linking)
VI  - 18
IP  - 2
DP  - 2000 Oct
TI  - A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and its 
      consensus DNA sequence.
PG  - 169-79
AB  - Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor 
      activated by hypoxia. When activated, HIF-1 mediates the differential expression 
      of genes such as erythropoietin and Vascular Endothelial Growth Factor (VEGF) 
      during hypoxia. It is composed of two different subunits, HIF-1alpha and ARNT 
      (Aryl Receptor Nuclear Translocator). These two subunits belong to the bHLH 
      (basic Helix-Loop-Helix) PAS (Per, Ahr/ARNT, Sim) family. The bHLH domain of 
      these factors is responsible for dimerization through the two helices and for DNA 
      binding through their basic domain. In this work, we used various methods of 
      molecular modeling in order to develop a 3D structure for the HIF-1 bHLH domain 
      bound to its DNA consensus sequence. Firstly, the 3D structure of the bHLH domain 
      of both subunits based on their amino acid sequence was defined. Secondly, we 
      compared this model with data from known crystal structures of basic leucine 
      zipper-DNA and bHLH-DNA complexes in order to determine a potential canvas for 
      HIF-1. Thirdly, we performed a manual approach of the HIF-1 bHLH domain onto the 
      DNA recognition site using this canvas. Finally, the protein-DNA complex 3D 
      structure was optimized using a Monte Carlo program called MONTY. The model 
      predicted a pattern of interactions between amino acids and DNA bases which 
      reflect for ARNT what is experimentally observed among different X-ray structures 
      of other bHLH transcription factors possessing the H (His), E (Glu), R (Arg) 
      triad, as ARNT does. On the other hand, only the Arg residue is conserved in HIF- 
      1alpha. We propose from this model that a serine replaces the histidine while an 
      alanine and a lysine also make contacts with DNA. From these results, we 
      postulate that the specificity of HIF-1 toward its DNA sequence could be driven 
      by the HIF-1alpha subunit. The predicted model will be verified by X-Ray 
      currently ongoing.
FAU - Michel, G
AU  - Michel G
AD  - Laboratoire de Chimie Moleculaire Structurale, Facultes Universitaires, 
      Notre-Dame-de-la-Paix, Namur, Belgium. gaetan.michel@fundp.ac.be
FAU - Minet, E
AU  - Minet E
FAU - Ernest, I
AU  - Ernest I
FAU - Roland, I
AU  - Roland I
FAU - Durant, F
AU  - Durant F
FAU - Remacle, J
AU  - Remacle J
FAU - Michiels, C
AU  - Michiels C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 11096-26-7 (Erythropoietin)
RN  - 452VLY9402 (Serine)
RN  - 4QD397987E (Histidine)
RN  - K3Z4F929H6 (Lysine)
RN  - OF5P57N2ZX (Alanine)
SB  - IM
MH  - Alanine/chemistry
MH  - Amino Acid Sequence
MH  - Animals
MH  - Crystallography
MH  - DNA-Binding Proteins/*chemistry
MH  - Dimerization
MH  - Erythropoietin/chemistry
MH  - Histidine/chemistry
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Lysine/chemistry
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Monte Carlo Method
MH  - Nuclear Proteins/*chemistry
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Sequence Analysis, DNA
MH  - Serine/chemistry
MH  - Software
MH  - Transcription Factors/chemistry
EDAT- 2000/11/23 11:00
MHDA- 2001/06/08 10:01
CRDT- 2000/11/23 11:00
PHST- 2000/11/23 11:00 [pubmed]
PHST- 2001/06/08 10:01 [medline]
PHST- 2000/11/23 11:00 [entrez]
AID - 10.1080/07391102.2000.10506656 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2000 Oct;18(2):169-79. doi: 10.1080/07391102.2000.10506656.