The 2020 Petr Sedmera Award
for the best published work in Nuclear Magnetic Resonance knows its winner. The competition is organized by the Czech Spectroscopic Society of Jan Marcus Marci and sponsored by the pharmaceutical company Teva. The awarded paper Quantitative Conformational Analysis of Functionally Important Electrostatic Interactions in the Intrinsically Disordered Region of Delta Subunit of Bacterial RNA Polymerase was published in Journal of the American Chemical Society by Lukáš Žídek and co-workers from CEITEC, Masaryk University.
Czech Large Research Infrastructures and SARS-CoV-2
As a part of the Large Research Infrastructures website there has been established a special section dedicated to SARS-CoV-2/Covid-19 research. It gathers offers of Czech research infrastructures services related to this topic.
Team Cryo ices Mass Spectrometry hopes in JBC Methods Madness tourney
In its inaugural Methods Madness tournament, the Journal of Biological Chemistry pitted influential research techniques against one another in a three-week competition for methods glory, and at 12:01 p.m. EST on March 31 cryo–EM/ET gave structural biologists around the world something to cheer about, beating mass spectrometry 51% to 49% — a margin thinner than shaved ice.
European Research Area (ERA) Corona Platform
Useful link for the latest information on EU grant opportunities affected by the COVID-19 pandemic.
Launch of Life Science Research Insfrastructure website with COVID-19 resources
A new website brings together the vast services of 13 Life Science Research Infrastructures in order to advance research in the life sciences. This website aims to be a common source of comprehensive information about the 13 European Life Science Research Infrastructures, their activities, offers, news and funding opportunities.
How SARS-CoV-2 binds to human cells
Scientists are racing to learn the secrets of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease COVID-19. On Friday, March 27 , 2020 Yuanyuan Zhan et al. from Westlake Institute of Advanced Study, Hangzhou, China, published in Science a study entitled Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 where they explain how it binds to human cells...
Highlights of Coronavirus Structural Studies
Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by Remdesivir
The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a target of the antiviral drug, Remdesivir. In the Science paper (published May 1, 2020) Yechun Xu, Shuyang Zhang, Yan Zhang, and H. Eric Xu report the cryo-EM structure of the SARS-CoV-2 RdRp either in the apo form at 2.8 Å resolution or in complex with a 50-base template-primer RNA and Remdesivir at 2.5 Å resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is covalently incorporated into the primer strand at the first replicated base pair and terminates chain elongation. The obtained structures provide critical insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.
Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2
Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading around the world. There is no existing vaccine or proven drug to pre- vent infections and stop virus proliferation. Although this virus is similar to human and animal SARS-CoVs and Middle East Respiratory Syndrome coronavirus (MERS-CoVs), the detailed information about SARS-CoV-2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies, and antivirals. Andrzej Joachimiak et. al applied high-throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases, Argonne National Laboratory, to produce SARS-CoV-2 proteins and structures. In the Protein Science paper they report two high-resolution crystal structures of endoribonuclease Nsp15/NendoU and compare these structures with previously reported homologs from SARS and MERS coronaviruses.
Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome– coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. The Science article by Qiang Zhou et. al. presents cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain
of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.
Reader's Corner Archive
How structure informs and transforms chemogenetics
Chemogenetic technologies such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are widely used to remotely control neuronal and non-neuronal signaling. DREADDs exist for most of the canonical G protein-coupled receptor signaling pathways, and provide a synthetic biology platform useful for elucidating the role of neuronal signaling for brain function. Here, Bryan L. Roth presents a focused review that shows how recent insights obtained from GPCR structural studies inform our understanding of these chemogenetic tools from a structural perspective.
Emerging structural insights into glycosyltransferase-mediated synthesis of glycans
Glycans linked to proteins and lipids play key roles in biology; thus, accurate replication of cellular glycans is crucial for maintaining function following cell division. Several recent crystal structures of glycosyltransferases with bound acceptor substrates reveal that these enzymes have common core structures that function as scaffolds upon which variable loops are inserted to confer substrate specificity and correctly orient the nucleophilic hydroxyl group. K. W. Moremen and R. S. Haltiwanger in Nature Chemical Biology review argue that the varied approaches for acceptor binding site assembly suggest that an ongoing evolution of these loop regions provides templates for assembly of the diverse glycan structures observed in biology.
Aminoacyl-tRNA synthetases as therapeutic targets
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Recent genomic, proteomic and functionomic advances have unveiled unexpected disease-associated mutations and altered expression, secretion and interactions in human ARSs, revealing hidden biological functions beyond their catalytic roles in protein synthesis. These studies have also brought to light their potential as a rich and unexplored source for new therapeutic targets and agents through multiple avenues, including direct targeting of the catalytic sites, controlling disease-associated protein–protein interactions and developing novel biologics from the secreted ARS proteins or their parts. Sunghoon Kim et. al. in Nature Reviews Drug Discovery address the emerging biology and therapeutic applications of human ARSs in diseases including autoimmune and rare diseases, and cancer.
Atomic Force Microscopy Based Tip-Enhanced Raman Spectroscopy in Biology
Tip-enhanced Raman spectroscopy (TERS), one of the burgeoning probing techniques, can provide not only the topography characterization with high resolution, but also can deliver the chemical or molecular information of a sample beyond the optical diffraction limitation. In this review, Bo Liu et. al. mainly focus on the applications of AFM-TERS in three biological systems: nucleic acids, proteins and pathogens. From the TERS characterization to the data analysis, this review demonstrates that AFM-TERS has great potential applications to visually characterizing the biomolecular structure and crucially detecting more nano-chemical information of biological systems.
Compressive Force Spectroscopy: From Living Cells to Single Proteins
One of the most successful applications of atomic force microscopy (AFM) in biology involves monitoring the effect of force on single biological molecules, often referred to as force spectroscopy. A less recognized variation of this method, the application of compressive force, allows studies from large samples (living cells) to smaller, multi-molecular complexes (viruses) down to single protein molecules. These studies have enabled the detailed characterization of individual cell states, subtle differences between seemingly identical viral structures, as well as the quantification of rate constants of functionally important, structural transitions in single proteins. Here, Daniel Mark Czajkowsky et. al. briefly review some of the recent achievements and highlight exciting areas of its future development.
RNA Dynamics by NMR Spectroscopy
To reveal dynamic processes and higher energy structures, new NMR methods have been developed to elucidate dynamics in RNA with atomic resolution. In this review, Katja Petzold et. al. provide an introduction to dynamics novices and an overview of methods that access most dynamic timescales, from picoseconds to hours.
How Good Can Single-Particle Cryo-EM Become? What Remains Before It Approaches Its Physical Limits?
Impressive though the achievements of single-particle cryo–electron microscopy are today, a substantial gap still remains between what is currently accomplished and what is theoretically possible. As is reviewed by Robert M. Glaeser, twofold or more improvements are possible as regards (a) the detective quantum efficiency of cameras at high resolution, (b) converting phase modulations to intensity modulations in the image, and (c) recovering the full amount of high-resolution signal in the presence of beam-induced motion of the specimen. In addition, potential for improvement is reviewed for other topics such as optimal choice of electron energy, use of aberration correctors, and quantum metrology. With the help of such improvements, it does not seem to be too much to imagine that determining the structural basis for every aspect of catalytic control, signaling, and regulation, in any type of cell of interest, could easily be accelerated fivefold or more.
Potential of cryo-EM for high-resolution structural analysis of gap junction channels
The review by Oshima et. al. in Current Opinions in Structural Biology outlines structural biology of gap junction channels utilizing crystallography and single-particle cryo-EM to shed light on the functional mechanisms of cell-cell communication that are essential for multicellular organisms.