High-resolution structures of the bifunctional enzyme and transcriptional coactivator DCoH and its complex with a product analogue.
DCoH, the dimerization cofactor of hepatocyte nuclear factor 1 (HNF-1), functions as both a transcriptional coactivator and a pterin dehydratase. To probe the relationship between these two functions, the X-ray crystal structures of the free enzyme and its complex with the product analogue 7,8-dihydrobiopterin were refined at 2.3 A resolution. The ligand binds at four sites per tetrameric enzyme, with little apparent conformational change in the protein. Each active-site cleft is located in a subunit interface, adjacent to a prominent saddle motif that has structural similarities to the TATA binding protein. The pterin binds within an arch of aromatic residues that extends across one dimer interface. The bound ligand makes contacts to three conserved histidines, and this arrangement restricts proposals for the enzymatic mechanism of dehydration. The dihedral symmetry of DCoH suggests that binding to the dimerization domain of HNF-1 likely involves the superposition of two-fold rotation axes of the two proteins.
Department of Molecular and Cell Biology, University of California at Berkeley 94720-3206, USA.
J D
JD
Cronk
J A
JA
Endrizzi
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T
Alber
D000818:Animals; D001665:Binding Sites; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins; D011487:Protein Conformation; D011622:Pterins / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496489:Hnf1a protein, rat; D009687:Nuclear Proteins; D011622:Pterins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D001708:Biopterins; C017226:7,8-dihydrobiopterin; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase