Ashwin Chari
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View article: Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome
Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome Open
Proteasomes catalyze protein degradation in cells and play an integral role in cellular homeostasis. Its activity decreases with age alongside the load of defective proteins, resulting from mutations or oxidative stress-induced damage. Suc…
View article: Protein degradation by human 20S proteasomes elucidates the interplay between peptide hydrolysis and splicing
Protein degradation by human 20S proteasomes elucidates the interplay between peptide hydrolysis and splicing Open
If and how proteasomes catalyze not only peptide hydrolysis but also peptide splicing is an open question that has divided the scientific community. The debate has so far been based on immunopeptidomics, in vitro digestions of synthetic po…
View article: Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design Open
Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been…
View article: Reconstruction of a fatty acid synthesis cycle from acyl carrier protein and cofactor structural snapshots
Reconstruction of a fatty acid synthesis cycle from acyl carrier protein and cofactor structural snapshots Open
Fatty acids (FAs) play a central metabolic role in living cells as constituents of membranes, cellular energy reserves, and second messenger precursors. A 2.6 MDa FA synthase (FAS), where the enzymatic reactions and structures are known, i…
View article: EIGER2 hybrid-photon-counting X-ray detectors for advanced synchrotron diffraction experiments
EIGER2 hybrid-photon-counting X-ray detectors for advanced synchrotron diffraction experiments Open
The ability to utilize a hybrid-photon-counting detector to its full potential can significantly influence data quality, data collection speed, as well as development of elaborate data acquisition schemes. This paper facilitates the optima…
View article: Prospects and Limitations of High-Resolution Single-Particle Cryo-Electron Microscopy
Prospects and Limitations of High-Resolution Single-Particle Cryo-Electron Microscopy Open
Single particle cryo-electron microscopy (cryo-EM) has matured into a robust method for the determination of biological macromolecule structures in the past decade, complementing X-ray crystallography and nuclear magnetic resonance. Consta…
View article: Multiple redox switches of the SARS-CoV-2 main protease in vitro provide new opportunities for drug design
Multiple redox switches of the SARS-CoV-2 main protease in vitro provide new opportunities for drug design Open
Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future outbreaks. The SARS-CoV-2 main protease (Mpro), a cysteine protease with essential funct…
View article: Ground-state destabilization by electrostatic repulsion is not a driving force in orotidine-5′-monophosphate decarboxylase catalysis
Ground-state destabilization by electrostatic repulsion is not a driving force in orotidine-5′-monophosphate decarboxylase catalysis Open
The origins of enzyme catalysis have been attributed to both transition-state stabilization as well as ground-state destabilization of the substrate. For the latter paradigm, the enzyme orotidine-5′-monophosphate decarboxylase (OMPDC) serv…
View article: Conformational rearrangements upon start codon recognition in human 48S translation initiation complex
Conformational rearrangements upon start codon recognition in human 48S translation initiation complex Open
Selection of the translation start codon is a key step during protein synthesis in human cells. We obtained cryo-EM structures of human 48S initiation complexes and characterized the intermediates of codon recognition by kinetic methods us…
View article: Redox regulation of the SARS-CoV-2 main protease provides new opportunities for drug design
Redox regulation of the SARS-CoV-2 main protease provides new opportunities for drug design Open
A bstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with ess…
View article: Conformational rearrangements upon start codon recognition in human 48S translation initiation complex
Conformational rearrangements upon start codon recognition in human 48S translation initiation complex Open
Selection of the translation start codon is a key step during protein synthesis in human cells. We obtained cryo-EM structures of human 48S initiation complexes and characterized the intermediates of codon recognition by kinetic methods us…
View article: Chromatography-Free Purification Strategies for Large Biological Macromolecular Complexes Involving Fractionated PEG Precipitation and Density Gradients
Chromatography-Free Purification Strategies for Large Biological Macromolecular Complexes Involving Fractionated PEG Precipitation and Density Gradients Open
A complex interplay between several biological macromolecules maintains cellular homeostasis. Generally, the demanding chemical reactions which sustain life are not performed by individual macromolecules, but rather by several proteins tha…
View article: X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease Open
A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, M pro , is essential to yield functional viral proteins,…
View article: The copper(II)-binding tripeptide GHK, a valuable crystallization and phasing tag for macromolecular crystallography
The copper(II)-binding tripeptide GHK, a valuable crystallization and phasing tag for macromolecular crystallography Open
The growth of diffraction-quality crystals and experimental phasing remain two of the main bottlenecks in protein crystallography. Here, the high-affinity copper(II)-binding tripeptide GHK was fused to the N-terminus of a GFP variant and a…
View article: Inhibition of SARS-CoV-2 main protease by allosteric drug-binding
Inhibition of SARS-CoV-2 main protease by allosteric drug-binding Open
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a s…
View article: Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution
Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution Open
Dissecting the degradation of the Alzheimer’s disease–related protein Tau by the 20 S proteasome at single-residue resolution.
View article: Breaking the next Cryo-EM resolution barrier – Atomic resolution determination of proteins!
Breaking the next Cryo-EM resolution barrier – Atomic resolution determination of proteins! Open
Summary Single particle cryo-EM is a powerful method to solve the three-dimensional structures of biological macromolecules. The technological development of electron microscopes, detectors, automated procedures in combination with user fr…
View article: Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease Open
Here we present the crystal structure of SARS-CoV-2 main protease (M pro ) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of M pro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronapht…
View article: Determination of the Binding Sites of Activators within the Proteasome Structure
Determination of the Binding Sites of Activators within the Proteasome Structure Open
The proteasome degrade most of the proteins in eukaryotic cells, thereby controlling the keycellular processes [...]
View article: Cryo-EM in drug discovery: achievements, limitations and prospects
Cryo-EM in drug discovery: achievements, limitations and prospects Open
Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug …