Press-room / Digest
Heterogeneity of the GFP fitness landscape and data-driven protein design
Understanding the relationship between genotype and phenotype, the fitness landscape, elucidates the fundamental laws of heredity and may ultimately create novel methods of protein design. In the present work a team of scientists from the Group of synthetic biology and the Group of molecular tags for optical nanoscopy IBCh RAS in the collaboration with foreign colleagues combined several approaches to engineer new variants of naturally occurring green fluorescent proteins by generating tens of thousands GFP mutant variants and assessing their ability to fluoresce. Moreover, machine learning algorithms were used for the predicting the performance of other GFP variants and expanding their fitness landscape. The published results indicate that to generate functional protein variants and to predict a protein’s function the algorithm only requires data on the effects of single-site mutations and their dependence on each other (low-order epistasis). The resulrs are published in the eLife journal. Learn more
Synthesis of 2-chloropurine ribosides with chiral amino acid amides at C6 and their evaluation as A1 adenosine receptor agonists
The team of scientists from the Department of biotechnology and the Laboratory of structural biology of ion channels IBCh RAS synthesized a series of adenosine analogs as purine ribonucleosides bearing amino acid amides at the C6 position of 2-chloropurine. Molecular docking by affinity for A1 adenosine receptors (A1ARs) was conducted. Colleagues from Volgograd State Medical University studied the A1AR stimulating activity in a model of an isolated mouse atrium. The investigation of A1AR stimulating activity of synthesized nucleosides was carried out in a model of an isolated mouse atrium. Derivatives with tyrosine, valine, and serine residues exhibit the properties of A1AR partial agonists. Animal experiments in the open field test have shown that these compounds have different profiles of psychoactive action. Serine derivative has intraocular pressure-lowering effect. The synthesized nucleosides can be the basis for further design and synthesis of new A1AR agonists. The results are published in the Bioorganic Chemistry. Learn more
Structure-based DHHC-acyltransferase selectivity for fatty acids
Researchers from the Group of in silico analysis of membrane proteins structure and the Laboratory of biomolecular modeling IBCH RAS in collaboration with Russian and foreign colleagues have suggested the molecular basis of fatty acid selectivity in the human DHHC family of protein acyltransferases (hDHHC). Based on calculated large set of molecular dynamics simulations it was demonstrated that selectivity of hDHHC20 towards palmitoyl (C16) is predetermined by the teepee-like shape of the enzyme: there is a bottleneck in the middle of the transmembrane segment, that regulates the positioning of reacting groups of both molecules. This hypothesis enabled the prediction of the hDHHC20 mutant V185G with a presumed selectivity shift towards C18. The study is published in the International Journal of Molecular Sciences.
Macrophage Blockade using Nature-Inspired Ferrihydrite for Enhanced Nanoparticle Delivery to Tumor
The rapid elimination of systemically administered drug nanocarriers by the mononuclear phagocyte system (MPS) compromises nanomedicine delivery efficacy. Scientists from the Laboratory of molecular immunology IBCh RAS in collaboration with Russian and Australian colleagues have developed a modern, effective and biocompatible agent for the temporary MPS blockade based on nanosized ferrihydrite particles that mimic endogenous iron associated with ferritin. Preliminary administration of ferrihydrite particles coated with carboxymethyl-dextran increased the blood circulation time of magnetic particles by 9 times and their targeted delivery to the tumor by 24 times, and also showed low toxicity. The work was published in the International Journal of Pharmaceutics.
Сytoskeleton protein Zyxin inhibits retinoic acid signaling by destabilizing maternal mRNA of nuclear receptor RXRγ
In a new study, researchers from the Laboratory of molecular bases of embryogenesis, Institute of Bioorganic Chemistry, Russian Academy of Sciences, demonstrated the versatility of the previously discovered mechanism of maternal genes mRNA destabilization caused by an interaction between the cytoskeletal protein Zyxin and the mRNA-binding factor Ybx1, showing that the same mechanism governs the retinoic acid signaling pathway during early embryonic development. The work was published in the International Journal of Molecular Sciences. Learn more