Structural basis for Porcupine inhibition
Open accessPublished version of a preprint
Abstract
Abstract Wnt signalling is essential for embryonic development and tissue homeostasis, and its dysregulation is associated with multiple types of cancer. Porcupine (PORCN), an endoplasmic reticulum (ER)-resident membrane-bound O-acyltransferase, catalyses the palmitoylation of all 19 human Wnts—a critical modification required for their secretion and activity. This central role makes PORCN an attractive therapeutic target for Wnt-driven cancers, with several inhibitors currently in clinical trials. Here, we present high-resolution cryo-electron microscopy structures of human PORCN in complex with the inhibitors C59 (2.4 Å) and ETC159 (2.6 Å), as well as in a ligand-free state (3.3 Å). These structures reveal critical ordered water molecules that form a hydrogen-bonding network within the active site, mediating inhibitor binding. Our docking simulations of diverse PORCN inhibitors demonstrate that despite their different chemical scaffolds, these compounds adopt similar conformations within the acyl-CoA binding site and are also engaged through a conserved water molecule. Our findings provide a structural foundation for the rational design of next-generation PORCN inhibitors with improved pharmacological properties for cancer therapy.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme
Sui, X., Wang, K., Gluchowski, N. L., Elliott, S. D., Liao, M., Walther, T. C., & Farese, R. V. (2020) · Nature · doi:10.1038/s41586-020-2289-6 · Cited by 120 · see citing works
Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT
Jiang, Y., Benz, T. L., & Long, S. B. (2021) · Science · doi:10.1126/science.abg4998 · Cited by 55 · see citing works
Mapping structural and dynamic divergence across the MBOAT family
Ansell, T. B., Healy, M., Coupland, C. E., Sansom, M. S. P., & Siebold, C. (2024) · Structure · doi:10.1016/j.str.2024.03.014 · Cited by 4 · see citing works
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- Authors
- Black, K. A., Mobbs, J. I., Venugopal, H., Dite, T. A., Leis, A., Wong, L. L., Dagley, L. F., Thal, D. M., & Glukhova, A.
- Affiliations
- The University of Melbourne (AU)
- Monash University (AU)
- Corresponding author
- Glukhova, Alisa
- ORCID
- Venue
- Communications Chemistry
- Published
- 2025-11-12
- Volume
- 8
- Issue
- 1
- Pages
- 348-348
- ISSN
- 2399-3669 (ISSN-L)
- PMC
- PMC12612157
- OpenAlex
- W4416142741
- Cited by
- 2
- References
- 4
- Citations by year
- 2026: 2
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Communications Chemistry (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
- Funders
- Monash University
- Medical Research Council
- National Health and Medical Research Council (1196951)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Wnt signaling, O-acyltransferase, hydrogen bond network, ordered water molecules, inhibitor binding, rational drug design, protein structure
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