Communications Biology (Jul 2023)

Structural insights into selective small molecule activation of PKG1α

  • Essam Metwally,
  • Victor Mak,
  • Aileen Soriano,
  • Matthias Zebisch,
  • H. Leonardo Silvestre,
  • Paul A. McEwan,
  • Grigori Ermakov,
  • Maribel Beaumont,
  • Paul Tawa,
  • John J. Barker,
  • Rose Yen,
  • Akash Patel,
  • Yeon-Hee Lim,
  • David Healy,
  • Jennifer Hanisak,
  • Alan C. Cheng,
  • Tom Greshock,
  • Thierry O. Fischmann

DOI
https://doi.org/10.1038/s42003-023-05095-4
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 13

Abstract

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Abstract cGMP-dependent protein kinase I-α (PKG1α) is a target for pulmonary arterial hypertension due to its role in the regulation of smooth muscle function. While most work has focused on regulation of cGMP turnover, we recently described several small molecule tool compounds which were capable of activating PKG1α via a cGMP independent pathway. Selected molecules were crystallized in the presence of PKG1α and were found to bind to an allosteric site proximal to the low-affinity nucleotide binding domain. These molecules act to displace the switch helix and cause activation of PKG1α representing a new mechanism for the activation and control of this critical therapeutic path. The described structures are vital to understanding the function and control of this key regulatory pathway.