7SSB

Co-structure of PKG1 regulatory domain with compound 33

Summary for 7SSB

• Entry DOI: 10.2210/pdb7ssb/pdb
• Descriptor: cGMP-dependent protein kinase 1, 4-({(2S,3S)-3-[(1S)-1-(3,5-dichlorophenyl)-2-hydroxyethoxy]-2-phenylpiperidin-1-yl}methyl)-3-nitrobenzoic acid (3 entities in total)
• Functional Keywords: binding sites, cyclic amp, cyclic gmp, cyclic gmp-dependent, protein kinase type ii, signaling protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31012.27

Authors

Fischmann, T.O. (deposition date: 2021-11-10, release date: 2022-08-24, Last modification date: 2023-10-18)

Primary citation

Mak, V.W.,Patel, A.M.,Yen, R.,Hanisak, J.,Lim, Y.H.,Bao, J.,Zheng, R.,Seganish, W.M.,Yu, Y.,Healy, D.R.,Ogawa, A.,Ren, Z.,Soriano, A.,Ermakov, G.P.,Beaumont, M.,Metwally, E.,Cheng, A.C.,Verras, A.,Fischmann, T.,Zebisch, M.,Silvestre, H.L.,McEwan, P.A.,Barker, J.,Rearden, P.,Greshock, T.J.
Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1 alpha.
J.Med.Chem., 65:10318-10340, 2022

PubMed Abstract: Activation of PKG1α is a compelling strategy for the treatment of cardiovascular diseases. As the main effector of cyclic guanosine monophosphate (cGMP), activation of PKG1α induces smooth muscle relaxation in blood vessels, lowers pulmonary blood pressure, prevents platelet aggregation, and protects against cardiac stress. The development of activators has been mostly limited to cGMP mimetics and synthetic peptides. Described herein is the optimization of a piperidine series of small molecules to yield activators that demonstrate phosphorylation of vasodilator-stimulated phosphoprotein as well as antiproliferative effects in human pulmonary arterial smooth muscle cells. Hydrogen/deuterium exchange mass spectrometry experiments with the small molecule activators revealed a mechanism of action consistent with cGMP-induced activation, and an X-ray co-crystal structure with a construct encompassing the regulatory domains illustrated a binding mode in an allosteric pocket proximal to the low-affinity cyclic nucleotide-binding domain.

PubMed: 35878399
DOI: 10.1021/acs.jmedchem.1c02109

Experimental method

X-RAY DIFFRACTION (1.4 Å)