8G93

Crystal structures of 17-beta-hydroxysteroid dehydrogenase 13

8G93 の概要

• エントリーDOI: 10.2210/pdb8g93/pdb
• 関連するPDBエントリー: 8G84 8G89
• 分子名称: Hydroxysteroid 17-beta dehydrogenase 13, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-fluoro-N-({(1r,4r)-4-[(2-fluorophenoxy)methyl]-1-hydroxycyclohexyl}methyl)-4-hydroxybenzamide, ... (4 entities in total)
• 機能のキーワード: 17 beta-hydroxysteroid dehydrogenase 13; lipid droplet associated protein; inhibitor, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Canis lupus familiaris (dog)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72809.95

構造登録者

Liu, S. (登録日: 2023-02-21, 公開日: 2023-08-09, 最終更新日: 2023-09-06)

主引用文献

Liu, S.,Sommese, R.F.,Nedoma, N.L.,Stevens, L.M.,Dutra, J.K.,Zhang, L.,Edmonds, D.J.,Wang, Y.,Garnsey, M.,Clasquin, M.F.
Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13.
Nat Commun, 14:5158-5158, 2023

PubMed Abstract: Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.

PubMed: 37620305
DOI: 10.1038/s41467-023-40766-0

実験手法

X-RAY DIFFRACTION (1.91 Å)