2AG5

Crystal Structure of Human DHRS6

Summary for 2AG5

• Entry DOI: 10.2210/pdb2ag5/pdb
• Descriptor: dehydrogenase/reductase (SDR family) member 6, SULFATE ION, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: protein-co-factor complex, structural genomics, structural genomics consortium, sgc, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9BUT1
• Total number of polymer chains: 4
• Total formula weight: 110281.30

Authors

Kunde, G.,Lukacik, P.,Papagrigoriou, E.,Sundstrom, M.,Arrowsmith, C.,Weigelt, J.,Edwards, A.,Von Delft, F.,Oppermann, U.,Structural Genomics Consortium (SGC) (deposition date: 2005-07-26, release date: 2005-08-09, Last modification date: 2024-03-13)

Primary citation

Guo, K.,Lukacik, P.,Papagrigoriou, E.,Meier, M.,Lee, W.H.,Adamski, J.,Oppermann, U.
Characterization of human DHRS6, an orphan short chain dehydrogenase/reductase enzyme: a novel, cytosolic type 2 R-beta-hydroxybutyrate dehydrogenase
J.Biol.Chem., 281:10291-10297, 2006

PubMed Abstract: Human DHRS6 is a previously uncharacterized member of the short chain dehydrogenases/reductase family and displays significant homologies to bacterial hydroxybutyrate dehydrogenases. Substrate screening reveals sole NAD(+)-dependent conversion of (R)-hydroxybutyrate to acetoacetate with K(m) values of about 10 mm, consistent with plasma levels of circulating ketone bodies in situations of starvation or ketoacidosis. The structure of human DHRS6 was determined at a resolution of 1.8 A in complex with NAD(H) and reveals a tetrameric organization with a short chain dehydrogenases/reductase-typical folding pattern. A highly conserved triad of Arg residues ("triple R" motif consisting of Arg(144), Arg(188), and Arg(205)) was found to bind a sulfate molecule at the active site. Docking analysis of R-beta-hydroxybutyrate into the active site reveals an experimentally consistent model of substrate carboxylate binding and catalytically competent orientation. GFP reporter gene analysis reveals a cytosolic localization upon transfection into mammalian cells. These data establish DHRS6 as a novel, cytosolic type 2 (R)-hydroxybutyrate dehydrogenase, distinct from its well characterized mitochondrial type 1 counterpart. The properties determined for DHRS6 suggest a possible physiological role in cytosolic ketone body utilization, either as a secondary system for energy supply in starvation or to generate precursors for lipid and sterol synthesis.

PubMed: 16380372
DOI: 10.1074/jbc.M511346200

Experimental method

X-RAY DIFFRACTION (1.84 Å)