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Highlights of Coronavirus Structural Studies

13 Apr

Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape (Science)

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, Wu, N. et al. generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. They used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, they engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.

13 Apr

Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution (Nature Communications)

In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the "down" conformation, indicating they are more prone to adopt the receptor-binding inactive state. However, Wang, XQ et al. found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. They further identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes. These results collectively indicate that tight RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.

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Research Highlights

the best of science obtained using CIISB Core Facilities

EMBO Journal 2021

The essential fungal‐specific translation elongation factor 3 (eEF3) has been implicated in tRNA binding and release. Combined in vitro and in vivo analyses show that its critical is in release of E‐site‐tRNA from the ribosome during late steps of translocation.

Daniel N. Wilson Research Group

Significance

In addition to the conserved translation elongation factors eEF1A and eEF2, fungi require a third essential elongation factor, eEF3. While eEF3 has been implicated in tRNA binding and release at the ribosomal A and E sites, its exact mechanism of action is unclear. Here, we show that eEF3 acts at the mRNA–tRNA translocation step by promoting the dissociation of the tRNA from the E site, but independent of aminoacyl‐tRNA recruitment to the A site. Depletion of eEF3 in vivo leads to a general slowdown in translation elongation due to accumulation of ribosomes with an occupied A site. Cryo‐EM analysis of native eEF3‐ribosome complexes shows that eEF3 facilitates late steps of translocation by favoring non‐rotated ribosomal states, as well as by opening the L1 stalk to release the E‐site tRNA. Additionally, our analysis provides structural insights into novel translation elongation states, enabling presentation of a revised yeast translation elongation cycle.

Ranjan, N; Pochopien, A ; hih-Chien Wu, C; Beckert, B; Blanchet, S; Green, R; Rodnina, M; Wilson, DN: Yeast translation elongation factor eEF3 promotes late stages of tRNA translocation during RF3-mediated recycling of RF1 EMBO J (2021) 40: e106449; https://doi.org/10.15252/embj.2020106449

 

Angew. Chem. Int. Edit. 2021

Nature Index Journal

A) Hemi‐protonated C⋅C+ base pair. B) Example of a sequence prone to form intramolecular i‐DNA. C) Possible loop arrangements in an i‐DNA structure; Simplified diagram of two linking directions between strands: Central loop can across either major (left, conformation I) or minor (right, conformation II) groove.

Jun-Jie Zhu Research Group

Significance

Recent studies indicate that i‐DNA, a four‐stranded cytosine‐rich DNA also known as the i‐motif, is actually formed in vivo; however, a systematic study on sequence effects on stability has been missing. Herein, an unprecedented number of different sequences (271) bearing four runs of 3–6 cytosines with different spacer lengths has been tested. While i‐DNA stability is nearly independent on total spacer length, the central spacer plays a special role on stability. Stability also depends on the length of the C‐tracts at both acidic and neutral pHs. This study provides a global picture on i‐DNA stability thanks to the large size of the introduced data set; it reveals unexpected features and allows to conclude that determinants of i‐DNA stability do not mirror those of G‐quadruplexes. Our results illustrate the structural roles of loops and C‐tracts on i‐DNA stability, confirm its formation in cells, and allow establishing rules to predict its stability.

Cheng, MP; Qiu, DH; Tamon, L; Istvankova, E; Viskova, P; Amrane, S; Guedin, A; Chen, JL; Lacroix, L; Ju, HX; Trantirek, L; Sahakyan, AB; Zhou, J; and Mergny, JL: Thermal and pH Stabilities of i-DNA: Confronting in vitro Experiments with Models and In-Cell NMR Data Angew. Chem. Int. Ed. on linehttps://doi.org/10.1002/anie.202016801

 

More publications Research Highlights archive

Reader’s Corner

literature to read, science to follow

In this section, a distinct selection of six highly stimulating research publications and reviews published during past 6 months is presented. It is our hope that links to exciting science, which deserves attention of the structural biology community, will help you to locate gems in the steadily expanding jungle of scientific literature. You are welcome to point out to any paper you found interesting by sending a link or citation to readerscorner@ciisb.org. The section is being updated regularly.

 

13 Apr

The story behind COVID-19 vaccines (Science Editorial)

Two activities predate the successful COVID-19 vaccines: the utilization of highly adaptable vaccine platforms such as RNA (among others) and the adaptation of structural biology tools to design agents (immunogens) that powerfully stimulate the immune system. Anthony S. Fauci recollects in this Science Editorial history of RNA vaccines developments and presents reasons why SARS-CoV-2 vaccines based on the new immunogen rapidly moved to clinical trials.

13 Apr

Structural interpretation of cryo-EM image reconstructions (Prog. Biophys. Mol. Biol.)

The productivity of single-particle cryo-EM as a structure determination method has rapidly increased as many novel biological structures are being elucidated. The ultimate result of the cryo-EM experiment is an atomic model that should faithfully represent the computed image reconstruction. Although the principal approach of atomic model building and refinement from maps resembles that of the X-ray crystallographic methods, there are important differences due to the unique properties resulting from the 3D image reconstructions. In this review, C. Sachse et. al. discuss the practiced work-flow from the cryo-EM image reconstruction to the atomic model. They give an overview of (i) resolution determination methods in cryo-EM including local and directional resolution variation, (ii) cryo-EM map contrast optimization including complementary map types that can help in identifying ambiguous density features, (iii) atomic model building and (iv) refinement in various resolution regimes including (v) their validation and (vi) discuss differences between X-ray and cryo-EM maps. Based on the methods originally developed for X-ray crystallography, the path from 3D image reconstruction to atomic coordinates has become an integral and important part of the cryo-EM structure determination work-flow that routinely delivers atomic models.

13 Apr

Towards high-throughput in situ structural biology using electron cryotomography (Prog. Biophys. Mol. Biol.)

Electron cryotomography is a rapidly evolving method for imaging macromolecules directly within the native environment of cells and tissues. Combined with sub-tomogram averaging, it allows structural and cell biologists to obtain sub-nanometre resolution structures in situ. However, low throughput in cryo-ET sample preparation and data acquisition, as well as difficulties in target localisation and subtomogram averaging image processing, limit its widespread usability. In this review, Bharat, TAM et. al. discuss new advances in the field that address these throughput and technical problems. They focus on recent efforts made to resolve issues in sample thinning, improvement in data collection speed at the microscope, strategies for localisation of macromolecules using correlated light and electron microscopy and advancements made to improve resolution in sub-tomogram averaging. These advances will considerably decrease the amount of time and effort required for cryo-ET and sub-tomogram averaging, ushering in a new era of structural biology where in situ macromolecular structure determination will be routine. 

13 Apr

NMR spectroscopy captures the essential role of dynamics in regulating biomolecular function (Cell)

Biomolecules are in constant motion. To understand how they function, and why malfunctions can cause disease, it is necessary to describe their three-dimensional structures in terms of dynamic conformational ensembles. Here, L. Kay and T.R. Alderson  demonstrate how nuclearmagnetic resonance (NMR) spectroscopy provides an essential, dynamic view of structural biology that captures biomolecular motions at atomic resolution. They focus on examples that emphasize the diversity of biomolecules and biochemical applications that are amenable to NMR, such as elucidating functional dynamics in large molecular machines, characterizing transient conformations implicated in the onset of disease, and obtaining atomic-level descriptions of intrinsically disordered regions that make weak interactions involved in liquid-liquid phase separation. Finally, theydiscuss the pivotal role that NMR has played in driving forward our understanding of the biomolecular dynamics-function paradigm.

29 Mar

A 'Build and Retrieve' methodology to simultaneously solve cryo-EM structures of membrane proteins (Nat. Methods)

Single-particle cryo-electron microscopy (cryo-EM) has become a powerful technique in the field of structural biology. However, the inability to reliably produce pure, homogeneous membrane protein samples hampers the progress of their structural determination. Here, E. W. Yu et. al. develop a bottom-up iterative method, Build and Retrieve (BaR), that enables the identification and determination of cryo-EM structures of a variety of inner and outer membrane proteins, including membrane protein complexes of different sizes and dimensions, from a heterogeneous, impure protein sample. They also use the BaR methodology to elucidate structural information from Escherichia coli K12 crude membrane and raw lysate. The findings demonstrate that it is possible to solve high-resolution structures of a number of relatively small (<100 kDa) and less abundant (<10%) unidentified membrane proteins within a single, heterogeneous sample. Importantly, these results highlight the potential of cryo-EM for systems structural proteomics.

29 Mar

Unravelling the structural complexity of glycolipids with cryogenic infrared spectroscopy (Nat. Commun.)

Glycolipids are complex glycoconjugates composed of a glycan headgroup and a lipid moiety. Their modular biosynthesis creates a vast amount of diverse and often isomeric structures, which fulfill highly specific biological functions. To date, no gold-standard analytical technique can provide a comprehensive structural elucidation of complex glycolipids, and insufficient tools for isomer distinction can lead to wrong assignments. Herein K. Pagel et. al. use cryogenic gas-phase infrared spectroscopy to systematically investigate different kinds of isomerism in immunologically relevant glycolipids. They show that all structural features, including isomeric glycan headgroups, anomeric configurations and different lipid moieties, can be unambiguously resolved by diagnostic spectroscopic fingerprints in a narrow spectral range. The results allow for the characterization of isomeric glycolipid mixtures and biological applications.

Reader’s Corner Archive

Quote of April

“Bad times have a scientific value. These are occasions a good learner would not miss.”

Ralph Waldo Emerson

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