A5063675352- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA modifications and cancer
- DNA and Nucleic Acid Chemistry
- Bioactive Compounds and Antitumor Agents
- Protein Kinase Regulation and GTPase Signaling
- Cancer therapeutics and mechanisms
- DNA Repair Mechanisms
- Synthesis and biological activity
- Ubiquitin and proteasome pathways
- Protein Tyrosine Phosphatases
- Supramolecular Self-Assembly in Materials
- Bacterial Genetics and Biotechnology
- Molecular Biology Techniques and Applications
- Surface Chemistry and Catalysis
- Signaling Pathways in Disease
- Down syndrome and intellectual disability research
- Calcium signaling and nucleotide metabolism
- Click Chemistry and Applications
- Genetics and Neurodevelopmental Disorders
- Viral Infections and Immunology Research
Italian Institute of Technology
2020-2025
AstraZeneca (Sweden)
2024
University of California, Riverside
2021
Abstract Group II introns are ubiquitous self-splicing ribozymes and retrotransposable elements evolutionarily chemically related to the eukaryotic spliceosome, with potential applications as gene-editing tools. Recent biochemical structural data have captured intron in multiple conformations at different stages of catalysis. Here, we employ enzymatic assays, X-ray crystallography, molecular simulations resolve spatiotemporal location function conformational changes occurring between first...
Abstract The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome retro-transposable elements pharmacological biotechnological importance. Integrating enzymatic, crystallographic, simulation studies, we demonstrate how these recognize small molecules through their conserved active site. These RNA-binding selectively inhibit two steps splicing by adopting distinctive poses at different stages catalysis, preventing crucial site conformational changes...
<title>Abstract</title> Many RNAs rely on their 3D structures for function. To acquire functional structures, certain form misfolded states (‘kinetic traps’), while other sequentially assemble onto well-folded scaffolds. Elucidating the principles of RNA sequential assembly is thus important to understand how avoid forming non-functional states. Integrating single-particle cryo-EM and image processing, SAXS, molecular simulations, we have visualized multidomain a self-splicing ribozyme...
Intracellular chloride concentration [Cl–]i is defective in several neurological disorders. In neurons, mainly regulated by the action of Na+–K+–Cl– importer NKCC1 and K+–Cl– exporter KCC2. Recently, we have reported discovery ARN23746 as lead candidate a novel class selective inhibitors NKCC1. Importantly, able to rescue core symptoms Down syndrome (DS) autism mouse models. Here, describe extensive characterization this chemical inhibitors, with focus on other promising derivatives....
CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues endothelial vascularize tumors. Here, we use computer-aided drug design discover a chemical entity (ARN22089) that has broad activity against panel cell lines, inhibits S6 phosphorylation MAPK activation, activates pro-inflammatory apoptotic signaling, blocks growth angiogenesis 3D vascularized microtumor models (VMT) vitro....
Recent in crystallo reaction intermediates have detailed how nucleic acid hydrolysis occurs the RNA ribonuclease H1 (RNase H1), a fundamental metalloenzyme involved maintaining human genome. At odds with previous characterization, these structures unexpectedly captured multiple metal ions (K+ and Mg2+) transiently bound vicinity of two-metal-ion active site. Using multi-microsecond all-atom molecular dynamics free-energy simulations, we investigated functional implications dynamic exchange...
This viewpoint discusses the predictive power and impact of computational analyses simulations to gain prospective, experimentally supported mechanistic insights into complex biological systems. Remarkably, two newly resolved cryoEM structures have confirmed previous, independent, prediction precise localization dynamics key catalytic ions in megadalton-large spliceosomal complexes. outstanding outcome endorses a prominent synergy experimental methods prospective exploration such large...
Abstract The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome retro-transposable elements pharmacological biotechnological importance. Integrating enzymatic, crystallographic, simulation studies, we demonstrate how these recognize small molecules through their conserved active site. These RNA-binding selectively inhibit two steps splicing by adopting distinctive poses at different stages catalysis, preventing crucial site conformational changes...
Abstract The CDC42 family of GTPases (RHOJ, RHOQ, CDC42) control both the ability tumor cells to invade surrounding tissues and endothelial vascularize tumors. While recent studies have developed small molecules that target RAS GTPases, little progress has been made in targeting related for cancer treatment. Here, we use computer-aided drug design identify a novel class inhibitors act on an allosteric pocket active form GTPase, RHOJ. These prevent RHOJ from binding their downstream effector...
Chemotherapeutic drugs disrupt the replication machinery and trigger apoptosis in cancer cells. For example, cisplatin-based chemotherapeutic form a covalent interaction with DNA, causing cell death. However, cells can respond to these by overtaking their effect. This phenomenon is referred as chemoresistance, one of main problems therapies. In this study, we have considered chemoresistance favored translesion DNA synthesis enzymes, like polymerase ƞ (Pol η). enzyme allows proliferation even...
SUMMARY CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues endothelial vascularize tumors. Here we use computer-aided drug design discover a new chemical entity (ARN22089) that targets blocks effector interactions without affecting binding between closely related (RAC1, RAS, RAL) their downstream effectors. Our lead compound has broad activity against panel cell lines, inhibits S6...