Selective Activation of a TRPC6 Ion Channel Over TRPC3 by Metalated Type-B Polycyclic Polyprenylated Acylphloroglucinols.
Philipp PeslalzFrank KrausFlavia IzzoAnton BleischYamina El HamdaouiIna SchulzAndreas Martin KanyAnna Katharina Herta HirschKristina FriedlandBernd PlietkerPublished in: Journal of medicinal chemistry (2023)
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 777 LLKL 780 -region of the C-terminus, thus providing critical insights into the binding mechanism of PPAP53 .
Keyphrases
- artificial intelligence
- vascular smooth muscle cells
- machine learning
- water soluble
- big data
- deep learning
- magnetic resonance
- depressive symptoms
- ms ms
- magnetic resonance imaging
- gram negative
- mass spectrometry
- gene expression
- binding protein
- electronic health record
- small molecule
- liquid chromatography
- multidrug resistant
- simultaneous determination
- high speed
- transcription factor
- tandem mass spectrometry
- transition metal