Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13.
- Resource Type
- Academic Journal
- Authors
- Liu S; Medicine Design, Pfizer Inc, Groton, CT, 06340, USA. Shenping.Liu@pfizer.com.; Sommese RF; Medicine Design, Pfizer Inc, Groton, CT, 06340, USA. Ruth.Sommese@pfizer.com.; Nedoma NL; Medicine Design, Pfizer Inc, Groton, CT, 06340, USA.; Stevens LM; Medicine Design, Pfizer Inc, Groton, CT, 06340, USA.; Dutra JK; Medicine Design, Pfizer Inc, Cambridge, MA, 02139, USA.; Zhang L; Medicine Design, Pfizer Inc, Cambridge, MA, 02139, USA.; Discovery Chemistry, Merck Research Laboratories, Cambridge, MA, USA.; Edmonds DJ; Medicine Design, Pfizer Inc, Cambridge, MA, 02139, USA.; Medicinal Chemistry, Roche, Basel, Switzerland.; Wang Y; Medicine Design, Pfizer Inc, Cambridge, MA, 02139, USA.; Garnsey M; Medicine Design, Pfizer Inc, Cambridge, MA, 02139, USA.; Clasquin MF; Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, 02139, USA.
- Source
- Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
- Subject
- Language
- English
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.
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