Structural model of PORCN .cif and .pdb files

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.