Emerging Topics in Biomolecular Magnetic Resonance – 4th edition
The series Emerging topics in Biomolecular Magnetic Resonance will continue on June 25th at 16:00 CEST with the following lecturers and topics:
Melinda J. Duer (University of Cambridge): Understanding extracellular matrix disease states with solid-state NMR?
Claudio Luchinat (University of Florence): NMR for metabolomics: again the ‘second best’ technique?
Emerging Topics in Biomolecular Magnetic Resonance – 3rd edition
The series Emerging topics in Biomolecular Magnetic Resonance will continue on June 18th at 16:00 CEST with the following lecturers and topics:
Tuo Wang (Louisiana State University): Elucidation of carbohydrate structure in plant biomass and fungal pathogens using solid-state NMR and DNP methods
Rina Rosenzweig (Weizmann Institute of Science): Molecular Chaperones in Protein Disaggregation - What we can learn from NMR
Emerging Topics in Biomolecular Magnetic Resonance – On-line lecture series
The series will continue on Thursday, June 11, 2020 at 16:00 CEST with two cutting-edge 30 minutes presentations:
Putative Amyloids in Human Health— Insights from NMR (Ann E. McDermott, Columbia University)
An RNA dynamic ensemble at atomic resolution (Hashim Al-Hashimi, Duke University)
New timsTOF Pro Mass Spectrometer installed at CEITEC.
New timsTOF Pro Mass Spectrometer (Bruker) has been installed at the Proteomics Core Facility, CEITEC MU. The new instrument brings another separation dimension (according collisional cross sections) in qualitative and quantitative characterization of complex protein samples as it is equipped by trapped ion mobility spectrometry (TIMS) module.
Emerging Topics in Biomolecular Magnetic Resonance – A new on-line lecture series
A new on-line lecture series on Emerging Topics in Biomolecular Magnetic Resonance, organized by Loren Andreas, Stefan Glöggler, Christian Griesinger, Mei Hong, Oscar Millet, Art Palmer, and Markus Zweckstetter, starts on Thursday, June 4, 2020.
Cryo-EM reaches yet another milestone – Comments on two recent cryo-EM atomic resolution studies
Two studies published during last two weeks have reported that single particle cryo-EM data can be now resolved to 1.20Å or 1.25Å, respectively. The groups of Sjors H.W. Scheres (LMB-MRC, Cambridge) and Holger Stark (MPI Göttingen) have for the first time shown that atomic resolution is attainable by single particle cryo-EM.
Highlights of Coronavirus Structural Studies
Molecular architecture of the SARS-CoV-2 virus
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped virus responsible for the COVID-19 pandemic. Despite recent advances in the structural elucidation of SARS-CoV-2 proteins and the complexes of the spike (S) proteins with the cellular receptor ACE2 or neutralizing antibodies, detailed architecture of the intact virus remains to be unveiled. Here, Li et al. from Zhejiang University School of Medicine, Hangzhou, China, report the molecular assembly of the authentic SARS-CoV-2 virus using cryo-electron tomography (cryo-ET) and subtomogram averaging (STA). Native structures of the S proteins in both pre- and post-fusion conformations were determined to average resolutions of 9-11 Å. Compositions of the N-linked glycans from the native spikes were analyzed by mass spectrometry, which revealed highly similar overall processing states of the native glycans to that of the recombinant glycoprotein glycans. The in-situ architecture of the ribonucleoproteins (RNP) and its higher-order assemblies were revealed. These characterizations have revealed the architecture of the SARS-CoV-2 virus to an unprecedented resolution, and shed lights on how the virus packs its ~30 Kb long single-segmented RNA in the ~80 nm diameter lumen. Overall, the results unveiled the molecular architecture and assembly of the SARS-CoV-2 in native context.
Door to the cell for COVID-19 opened, leading way to therapies
A very recent study by Lan et al. published in Nature (https://doi.org/10.1038/s41586-020-2180-5) determined the crystal structure of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 receptor-binding domain (RBD) bound to angiotensin-converting enzyme 2 (ACE2). The structure reveals the mechanism of SARS-CoV-2 RBD recognition by its receptor ACE2, which is highly conserved in ACE2 recognition of SARS-CoV RBD. The study provides structural information on developing small molecules targeting SARS-CoV-2 RBD/ACE2 and implies the existence of other mechanisms than receptor binding for the markedly different infection activity of the two evolutionarily close viruses.
Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 2020(1,2). Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here Corti and Veeler et. al. describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which they identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, they show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirussubgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.
Reader's Corner Archive
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.
Molecular dynamics simulations of macromolecular crystals
The paper of David Case and David Cerutti in WIREs Computational Molecular Science evaluates past fusions of simulations and crystallography and looks ahead to the ways that simulations of crystal structures will enhance structural biology in the future.
Combining Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR) Spectroscopy for Integrative Structural Biology of Protein–RNA Complexes
In this publication Fred Allain et.al. reviews recent advances in hybrid structural approaches with a focus on combining MS analysis of cross-linked protein–RNA complexes and NMR spectroscopy.