News

European Researchers’ Night 2019 (27th September 2019)

European Researchers’ Night 2019 in Rijeka took place in Tower Center on friday, 27th September 2019. BioSFLab participated with the topic Supercomputer Bura: our window to the world of molecules.

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View the program of the European Researchers' Night 2019 in Rijeka (in Croatian).

View MojaRijeka.hr’s video report about European Researchers’ Night 2018 in Rijeka (in Croatian)

Read University of Rijeka’s report about European Researchers’ Night 2018 (in Croatian)

Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs published in ACS Chemical Biology (5th June 2019)

Our research paper titled Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs authored by Jonathan Pansieri, Lucija Ostojić, Igor A. Iashchishyn, Mazin Magzoub, Cecilia Wallin, Sebastian K. T. S. Wärmländer, Astrid Gräslund, Mai Nguyen Ngoc, Vytautas Smirnovas, Željko Svedružić, and Ludmilla A. Morozova-Roche (research group) has been published today in ACS Chemical Biology.

Abstract

Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from Aβ peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self-assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.

Read the full paper in ACS Chemical Biology volume 14 issue 7.

In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1 published in PLOS ONE (11th April 2017)

Our research paper titled In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1 authored by Vedran Miletić, Ivica Odorčić, Patrik Nikolić, and Željko Svedružić has been published today in PLOS ONE, the flagship Open Access journal.

Background

We use our earlier experimental studies of the catalytic mechanism of DNA methyltransferases to prepare in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for analysis of human epigenome and for the creation of iPS cells.

Results

We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivatives as novel mechanism-based inhibitors of mammalian DNA methyltransferase Dnmt1. The inhibitors have been designed to bind simultaneously in the active site and the cofactor site and thus act as transition-state analogues. Molecular dynamics studies showed that the lead compound can form between 6 to 9 binding interactions with Dnmt1. QM/MM analysis showed that the upon binding to Dnmt1 the inhibitor can form a covalent adduct with active site Cys1226 and thus act as a mechanism-based suicide-inhibitor. The inhibitor can target DNA-bond and DNA-free form of Dnmt1, however the suicide-inhibition step is more likely to happen when DNA is bound to Dnmt1. The validity of presented analysis is described in detail using 69 modifications in the lead compound structure. In total 18 of the presented 69 modifications can be used to prepare a family of highly specific inhibitors that can differentiate even between closely related enzymes such as Dnmt1 and Dnmt3a DNA methyltransferases.

Conclusions

Presented results can be used for preparation of some highly specific and potent inhibitors of mammalian DNA methylation with specific pharmacological properties.

Read the full paper in PLOS ONE volume 12 issue 4.