Linked Life Data

11089639

Source:http://linkedlifedata.com/resource/pubmed/id/11089639

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2001-2-12
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0739-1102
pubmed:author
pubmed:issnType
Print
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
169-79
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11089639-Alanine, pubmed-meshheading:11089639-Amino Acid Sequence, pubmed-meshheading:11089639-Animals, pubmed-meshheading:11089639-Crystallography, pubmed-meshheading:11089639-DNA-Binding Proteins, pubmed-meshheading:11089639-Dimerization, pubmed-meshheading:11089639-Erythropoietin, pubmed-meshheading:11089639-Histidine, pubmed-meshheading:11089639-Hypoxia-Inducible Factor 1, pubmed-meshheading:11089639-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:11089639-Lysine, pubmed-meshheading:11089639-Models, Molecular, pubmed-meshheading:11089639-Molecular Sequence Data, pubmed-meshheading:11089639-Monte Carlo Method, pubmed-meshheading:11089639-Nuclear Proteins, pubmed-meshheading:11089639-Protein Binding, pubmed-meshheading:11089639-Protein Conformation, pubmed-meshheading:11089639-Protein Structure, Secondary, pubmed-meshheading:11089639-Protein Structure, Tertiary, pubmed-meshheading:11089639-Sequence Analysis, DNA, pubmed-meshheading:11089639-Serine, pubmed-meshheading:11089639-Software, pubmed-meshheading:11089639-Transcription Factors
pubmed:year
2000
pubmed:articleTitle
A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and its consensus DNA sequence.
pubmed:affiliation
Laboratoire de Chimie Moléculaire Structurale, Facultés Universitaires, Notre-Dame-de-la-Paix, Namur, Belgium. gaetan.michel@fundp.ac.be
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't