Structural basis for selective inhibition of human PKG Iα by the balanol-like compound N46

The Journal of Biological Chemistry
Liying QinChoel Kim

Abstract

Activation of protein kinase G (PKG) Iα in nociceptive neurons induces long-term hyperexcitability that causes chronic pain. Recently, a derivative of the fungal metabolite balanol, N46, has been reported to inhibit PKG Iα with high potency and selectivity and attenuate thermal hyperalgesia and osteoarthritic pain. Here we determined co-crystal structures of the PKG Iα C-domain and cAMP-dependent protein kinase (PKA) Cα, each bound with N46, at 1.98 Å and 2.65 Å, respectively. N46 binds the active site with its external phenyl ring, specifically interacting with the glycine-rich loop and the αC helix. Phe-371 at the PKG Iα glycine-rich loop is oriented parallel to the phenyl ring of N46, forming a strong π-stacking interaction, whereas the analogous Phe-54 in PKA Cα rotates 30° and forms a weaker interaction. Structural comparison revealed that steric hindrance between the preceding Ser-53 and the propoxy group of the phenyl ring may explain the weaker interaction with PKA Cα. The analogous Gly-370 in PKG Iα, however, causes little steric hindrance with Phe-371. Moreover, Ile-406 on the αC helix forms a hydrophobic interaction with N46 whereas its counterpart in PKA, Thr-88, does not. Substituting these residues in PKG Iα with ...Continue Reading

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Citations

Jan 18, 2020·Journal of Translational Medicine·Choel KimDarren E Casteel
Jan 12, 2020·The Journal of Eukaryotic Microbiology·Edel Pérez-LópezPeta C Bonham-Smith
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Francis GiraudPascale Moreau
May 4, 2021·British Journal of Pharmacology·Hannes SchmidtAchim Schmidtko

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