A novel inhibitor of active protein kinase G attenuates chronic inflammatory and osteoarthritic pain

Sung, Ying-Ju; Sofoluke, Nelson; Nkamany, Mary; Deng, Shi‐Xian; Xie, Yuning; Greenwood, Jeremy R.; Farid, Ramy; Landry, Donald W.; Ambron, Richard T.

doi:10.1097/j.pain.0000000000000832

Cited by 17 publications

(23 citation statements)

References 48 publications

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“…In particular, Phe-350 at the glycine-rich loop occupies the part of the pocket the C-ring binds, suggesting that N46 would interact poorly with PKC␣. Consistent with the model, Sung et al (18) reported that, at 0.75 M of N46, PKC␦ had 68% residual activity, whereas PKG I␣ was completely inhibited with 0% residual activity .…”

Section: N46 Specificity For Pkg I␣mentioning

confidence: 57%

“…The reported inhibition constant of balanol for PKA C␣ is 1.6 nM, whereas N46 inhibits PKA with an IC 50 of 1.0 M, showing an over 600-fold increase (18). Comparing the PKA C␣-N46 complex with the PKA C␣-balanol complex reveals that this reduction is mostly due to loss of hydrogen bonds (Fig.…”

Section: Resultsmentioning

confidence: 91%

“…In designing N46, the propoxy group was added to the phenyl ring to provide a preferential interaction with Ile-406 of PKG I␣ over PKA C␣, which has a threonine (Thr-88) at the analogous position ( Fig. S3) (18). However, the structure shows that the methoxy group points toward the side chain of Ile-406 instead, whereas the propoxy group points toward the glycine-rich loop, each providing hydrophobic interactions.…”

Section: Resultsmentioning

confidence: 99%

“…PKG I␣ is also a crucial modulator of cortical neuronal activity in pathological pain; thus, it represents a novel target for developing analgesic therapeutic agents (17). A recent study demonstrated that N46, a derivative of the fungal metabolite balanol, inhibits PKG I␣ with high potency and selectivity, resulting in attenuation of thermal hyperalgesia and osteoarthritic pain in rats (18).…”

mentioning

confidence: 99%

“…To improve inhibitor selectivity for PKG I␣, a homology model of PKG I␣ docked with balanol was generated based on the crystal structure of the PKA C␣-balanol complex. Several amino acid differences near their binding pockets were identified, and balanol was modified to preferentially interact with PKG I␣-specific residues (18). In particular, the homology model showed that Thr-88 of PKA C␣ corresponds to Ile-406 in PKG I␣ (16).…”

mentioning

confidence: 99%

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

Qin

Sankaran

Aminzai

et al. 2018

Journal of Biological Chemistry

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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 those in PKA Cα increases the IC values for N46, whereas replacing these residues in PKA Cα with those in PKG Iα reduces the IC, consistent with our structural findings. In conclusion, our results explain the structural basis for N46-mediated selective inhibition of human PKG Iα and provide a starting point for structure-guided design of selective PKG Iα inhibitors.

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Section: N46 Specificity For Pkg I␣mentioning

confidence: 57%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Qin

Sankaran

Aminzai

et al. 2018

Journal of Biological Chemistry

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The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development

Das

Chen

Yan

et al. 2021

Pflugers Arch - Eur J Physiol

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The second messengers, cGMP and Ca2+, have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor cell death. This problem is exacerbated by the close connections and crosstalk between cGMP-signalling and calcium (Ca2+)-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca2+-signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca2+ permeable channels, relation to energy metabolism, calpain-type proteases, and how the related metabolic processes may trigger and execute photoreceptor cell death. A focus is then put on cGMP-dependent mechanisms and how exceedingly high photoreceptor cGMP levels set in motion cascades of Ca2+-dependent and independent processes that eventually bring about photoreceptor cell death. Finally, an outlook is given into mutation-independent therapeutic approaches that exploit specific features of cGMP-signalling. Such approaches might be combined with suitable drug delivery systems for translation into clinical applications.

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Protein kinase G is a molecular switch for pain

Sung

Ambron

2022

The Neurobiology, Physiology, and Psychology of Pain

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A novel inhibitor of active protein kinase G attenuates chronic inflammatory and osteoarthritic pain

Abstract: Supplemental Digital Content is Available in the Text.A novel and potent protein kinase G-1α (PKG-1α) inhibitor is used to demonstrate the important roles of PKG in capsaicin-induced acute pain and in persistent inflammatory pain.

Cited by 17 publications

References 48 publications

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

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

The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development

Protein kinase G is a molecular switch for pain

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