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PreprintCited by 29Enzyme Structure and FunctionLiver Disease Diagnosis and TreatmentProtein Structure and Dynamics

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Crystal structures of 17-beta-hydroxysteroid dehydrogenase 13

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Liu, Shenping, Sommese, Ruth, Nedoma, Nicole, Stevens, Lucy, Dutra, Jason, Wang, Yang, Garnsey, Michelle, Clasquin, Michelle·2023·Nature Communications
DOI 10.21203/rs.3.rs-2688507/v1PMC PMC10449848

Preprint — published as 10.1038/s41467-023-40766-0

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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 the first known crystal structures of full length HSD17B13 in complex with its NAD+ cofactor and with small molecule inhibitors from two distinct series. 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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Metadata

Authors
Liu, S., Sommese, R., Nedoma, N., Stevens, L., Dutra, J., Wang, Y., Garnsey, M., & Clasquin, M.
Affiliations
Pfizer (United States) (US)
Corresponding author
  • Liu, Shenping
  • Sommese, Ruth
ORCID
Venue
Nature Communications
Publisher
Research Square Platform LLC
Published
2023-04-20
Volume
14
Issue
1
Pages
5158-5158
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-2688507/v1
PMC
PMC10449848
OpenAlex
W4386136752
Cited by
29
References
1
Citations by year
2026: 10 · 2025: 10 · 2024: 9
FWCI
2.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
HSD17B13, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, steatosis, NAD+ cofactor, crystal structure, small molecule inhibitors, active site, loss-of-function mutations, membrane anchoring, structure-based drug design, hepatocellular carcinoma
MeSH terms
Lipid Droplet Associated Proteins, Carcinoma, Hepatocellular, Humans, Lipids, Liver Neoplasms, 17-Hydroxysteroid Dehydrogenases, Non-alcoholic Fatty Liver Disease

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