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Structural model of PORCN .cif and .pdb files

Citation

Yu, Jia et al. (2021), Structural model of PORCN .cif and .pdb files, Dryad, Dataset, https://doi.org/10.5061/dryad.crjdfn35j

Abstract

Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Here, based on homology to mammalian MBOAT proteins we develop and validate a molecular structural model of PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model provides mechanistic insights into PORCN substrate recognition and catalysis as well as the inhibition of its enzymatic activity and can facilitate the development of improved inhibitors and the understanding of disease relevant PORCN mutants.

Methods

The homology model of PORCN was generated as described in Yu et al. bioRxiV 2021 and Journal of Cell Science.

Usage Notes

These files can be opened with structure visualization programs such as PyMol and Chimera.

Funding

National Medical Research Council, Award: STaR MOH-000155