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Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand. J Biol Chem 2002 Oct 11;277(41):37973-6

Date

08/24/2002

Pubmed ID

12193589

DOI

10.1074/jbc.C200420200

Scopus ID

2-s2.0-0037063997   221 Citations

Abstract

HNF4 alpha is an orphan member of the nuclear receptor family with prominent functions in liver, gut, kidney and pancreatic beta cells. We have solved the x-ray crystal structure of the HNF4 alpha ligand binding domain, which adopts a canonical fold. Two conformational states are present within each homodimer: an open form with alpha helix 12 (alpha 12) extended and collinear with alpha 10 and a closed form with alpha 12 folded against the body of the domain. Although the protein was crystallized without added ligands, the ligand binding pockets of both closed and open forms contain fatty acids. The carboxylic acid headgroup of the fatty acid ion pairs with the guanidinium group of Arg(226) at one end of the ligand binding pocket, while the aliphatic chain fills a long, narrow channel that is lined with hydrophobic residues. These findings suggest that fatty acids are endogenous ligands for HNF4 alpha and establish a framework for understanding how HNF4 alpha activity is enhanced by ligand binding and diminished by MODY1 mutations.

Author List

Dhe-Paganon S, Duda K, Iwamoto M, Chi YI, Shoelson SE

Author

Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Binding Sites
Crystallography, X-Ray
DNA-Binding Proteins
Dimerization
Fatty Acids
Hepatocyte Nuclear Factor 4
Humans
Ligands
Models, Molecular
Mutation
Phosphoproteins
Protein Structure, Secondary
Protein Structure, Tertiary
Rats
Receptors, Cytoplasmic and Nuclear
Transcription Factors