5SC9

Structure of liver pyruvate kinase in complex with anthraquinone derivative 29

Summary for 5SC9

• Entry DOI: 10.2210/pdb5sc9/pdb
• Group deposition: ADP-competitive inhibitors of PKL (G_1002224)
• Descriptor: Pyruvate kinase, 1,6-di-O-phosphono-beta-D-fructofuranose, OXALATE ION, ... (6 entities in total)
• Functional Keywords: pyruvate kinase, active site, inhibition, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 392971.07

Authors

Lulla, A.,Foller, A.,Nain-Perez, A.,Grotli, M.,Brear, P.,Hyvonen, M. (deposition date: 2021-12-01, release date: 2022-03-16, Last modification date: 2024-05-22)

Primary citation

Nain-Perez, A.,Foller Fuchtbauer, A.,Haversen, L.,Lulla, A.,Gao, C.,Matic, J.,Monjas, L.,Rodriguez, A.,Brear, P.,Kim, W.,Hyvonen, M.,Boren, J.,Mardinoglu, A.,Uhlen, M.,Grotli, M.
Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase.
Eur.J.Med.Chem., 234:114270-114270, 2022

PubMed Abstract: Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure-activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.

PubMed: 35290845
DOI: 10.1016/j.ejmech.2022.114270

Experimental method

X-RAY DIFFRACTION (1.685 Å)