Month: March 2022

Amalyn Nain-Pereza, Anders Foller Füchtbauera, Liliana Håversen, Aleksei Lulla, Chunxia Gao, Josipa Matic, Leticia, Monjasa Alexandra Rodríguez, Paul Brear, Woonghee Kim, Marko Hyvönen, Jan Borén, Adil Mardinoglu, Mathias Uhlen, Morten Grøtli

European Journal of Medicinal Chemistry 23:114270 (2021)
DOI: 10.1016/j.ejmech.2022.114270
Pubmed: 35290845

PDB coordinates:

5SCL (3D view), 5SDT (3D view), 5SC8 (3D view), 5SCB (3D view), 5SC9 (3D view), 5SCA (3D view), 5SCK (3D view), 7QZU (3D view), 5SCE (3D view), 5SCC (3D view), 5SCD (3D view), 5SCF (3D view), 5SCH (3D view), 5SCG (3D view), 5SCI (3D view), 5SCJ (3D view), 7QDN (3D view)

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 (IC50) values in the 200 nM range. Continue reading →

Marie Synakewicz, Rohan S Eapen, Albert Perez-Riba, Pamela J E Rowling, Daniela Bauer, Andreas Weißl, Gerhard Fischer, Marko Hyvönen, Matthias Rief, Laura S Itzhaki, Johannes Stigler

ACS Nano, 2022 (online before print version)
DOI: doi: 10.1021/acsnano.1c09162
Pubmed: 35258937

Abstract

Tandem-repeat proteins comprise small secondary structure motifs that stack to form one-dimensional arrays with distinctive mechanical properties that are proposed to direct their cellular functions. Here, we use single-molecule optical tweezers to study the folding of consensus-designed tetratricopeptide repeats (CTPRs), superhelical arrays of short helix-turn-helix motifs. We find that CTPRs display a spring-like mechanical response in which individual repeats undergo rapid equilibrium fluctuations between partially folded and unfolded conformations. We rationalize the force response using Ising models and dissect the folding pathway of CTPRs under mechanical load, revealing how the repeat arrays form from the center toward both termini simultaneously. Continue reading →