Vasile, S. | Search bioRxiv

bioRxiv2019

GPCRmd uncovers the dynamics of the 3D-GPCRome

G protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new 3D molecular structures of GPCRs (3D-GPCRome) during the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. While experimentally-resolved structures undoubtedly provide valuable snapshots of specific GPCR conformational states, they give only limited information on their flexibility and dynamics associated with function. Molecular dynamics (MD) simulations have become a widely established technique to explore the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations requires efficient storage resources and specialized software, hence limiting the dissemination of these data to specialists in the field. Here we present the GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyse and share GPCR MD data. GPCRmd originates from a community-driven effort to create the first open, interactive, and standardized database of GPCR MD simulations. We demonstrate the power of this resource by performing comparative analyses of multiple GPCR simulations on two mechanisms critical to receptor function: internal water networks and sodium ion interaction.

biophysics↗

bioRxiv2019

Suramin potently inhibits binding of the mammalian high mobility group protein AT-hook 2 to DNA

The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein which plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen high throughput screening (HTS) assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we discovered that suramin, a negatively charged antiparasitic drug potently inhibits the HMGA2-DNA interaction. Our results also show that the inhibition is through suramin binding to the AT-hooks of HMGA2, therefore blocking its DNA binding capacity. Furthermore, we demonstrate that suramin can induce brain tumor stem cells differentiation into cells with neurite-like structures, a process triggered by disrupting HMGA2-DNA interactions. Since suramin has strong antitumor and anti-metastasis activities, our discovery suggests that HMGA2 and HMGA2-like proteins may be the cellular target of this century-old drug.

biochemistry↗