7QZU

Structure of liver pyruvate kinase in complex with anthraquinone derivative 47

Summary for 7QZU

• Entry DOI: 10.2210/pdb7qzu/pdb
• Related: 5SC8 5SC9 5SCA 5SCB 5SCC 5SCD 5SCE 5SCF 5SCH 5SCI 5SCJ 5SCK 5SCL 5SDT 7QDN
• Descriptor: PKL, 1,6-di-O-phosphono-beta-D-fructofuranose, OXALATE ION, ... (7 entities in total)
• Functional Keywords: pyruvate kinase, active site, inhibition, transferase
• Biological source: Homo sapiens
• Total number of polymer chains: 8
• Total formula weight: 393590.35

Authors

Lulla, A.,Foller, A.,Nain-Perez, A.,Grotli, M.,Brear, P.,Hyvonen, M. (deposition date: 2022-01-31, release date: 2022-04-06, Last modification date: 2024-01-31)

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 (1.964 Å)