Selective Activation of a TRPC6 Ion Channel Over TRPC3 by Metalated Type‑B Polycyclic Polyprenylated Acylphloroglucinols

Selective modulation
of TRPC6 ion channels is a promising
therapeutic
approach for neurodegenerative diseases and depression. A significant
advancement showcases the selective activation of TRPC6 through metalated
type-B PPAP, termed PPAP53. This success stems from PPAP53’s 1,3-diketone motif facilitating metal coordination. PPAP53 is water-soluble and as potent as hyperforin, the gold
standard in this field. In contrast to type-A, type-B PPAPs offer
advantages such as gram-scale synthesis, easy derivatization, and
long-term stability. Our investigations reveal PPAP53 selectively binding to the C-terminus of TRPC6. Although cryoelectron
microscopy has resolved the majority of the TRPC6 structure, the binding
site in the C-terminus remained unresolved. To address this issue,
we employed state-of-the-art artificial-intelligence-based protein
structure prediction algorithms to predict the missing region. Our
computational results, validated against experimental data, indicate
that PPAP53 binds to the 777LLKL780-region of the C-terminus, thus providing critical insights into
the binding mechanism of PPAP53.