Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand.
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.
Joslin Diabetes Center & Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Sirano
S
Dhe-Paganon
Karen
K
Duda
Melanie
M
Iwamoto
Young-In
YI
Chi
Steven E
SE
Shoelson
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D019281:Dimerization; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D008024:Ligands; C403128:MLX protein, human; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors