scholarly journals Structure of SARS-CoV-2 ORF8, a rapidly evolving coronavirus protein implicated in immune evasion

2020 ◽  
Author(s):  
Thomas G. Flower ◽  
Cosmo Z. Buffalo ◽  
Richard M. Hooy ◽  
Marc Allaire ◽  
Xuefeng Ren ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Evasion ◽  
Immune Suppression ◽  
Molecular Basis ◽  
Large Scale ◽  
Terminal Sequence ◽  
Specific Sequence ◽  
X Ray ◽  
X Ray Crystallography ◽  
Rapid Spread

AbstractThe molecular basis for the severity and rapid spread of the COVID-19 disease caused by SARS-CoV-2 is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04 Å resolution by x-ray crystallography. The structure reveals a ~60 residue core similar to SARS-CoV ORF7a with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate non-covalent interface is formed by another SARS-CoV-2-specific sequence, 73YIDI76. Together the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

scholarly journals Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein

2020 ◽  
Vol 118 (2) ◽  
pp. e2021785118
Author(s):  
Thomas G. Flower ◽  
Cosmo Z. Buffalo ◽  
Richard M. Hooy ◽  
Marc Allaire ◽  
Xuefeng Ren ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Evasion ◽  
Immune Suppression ◽  
Molecular Basis ◽  
Large Scale ◽  
Terminal Sequence ◽  
Specific Sequence ◽  
X Ray ◽  
X Ray Crystallography ◽  
Rapid Spread

The molecular basis for the severity and rapid spread of the COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-Å resolution by X-ray crystallography. The structure reveals a ∼60-residue core similar to SARS-CoV-2 ORF7a, with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate noncovalent interface is formed by another SARS-CoV-2−specific sequence, 73YIDI76. Together, the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

scholarly journals xMDFF: molecular dynamics flexible fitting of low-resolution X-ray structures

2014 ◽  
Vol 70 (9) ◽  
pp. 2344-2355 ◽  
Author(s):  
Ryan McGreevy ◽  
Abhishek Singharoy ◽  
Qufei Li ◽  
Jingfen Zhang ◽  
Dong Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Protein Structures ◽  
Data Bank ◽  
Real Space ◽  
Low Resolution ◽  
X Ray ◽  
X Ray Crystallography ◽  
Atomic Structures ◽  
Electron Density Map

X-ray crystallography remains the most dominant method for solving atomic structures. However, for relatively large systems, the availability of only medium-to-low-resolution diffraction data often limits the determination of all-atom details. A new molecular dynamics flexible fitting (MDFF)-based approach, xMDFF, for determining structures from such low-resolution crystallographic data is reported. xMDFF employs a real-space refinement scheme that flexibly fits atomic models into an iteratively updating electron-density map. It addresses significant large-scale deformations of the initial model to fit the low-resolution density, as tested with synthetic low-resolution maps of D-ribose-binding protein. xMDFF has been successfully applied to re-refine six low-resolution protein structures of varying sizes that had already been submitted to the Protein Data Bank. Finally,viasystematic refinement of a series of data from 3.6 to 7 Å resolution, xMDFF refinements together with electrophysiology experiments were used to validate the first all-atom structure of the voltage-sensing protein Ci-VSP.

scholarly journals Molecular Basis of the “Alternate Access Model” in the Cation-Substrate Symporter Mhp1 from Computer Simulations and X-Ray Crystallography

2010 ◽  
Vol 98 (3) ◽  
pp. 628a
Author(s):  
Oliver Beckstein ◽  
Tatsuro Shimamura ◽  
Simone Weyand ◽  
Nicholas G. Rutherford ◽  
Jonathan M. Hadden ◽  
...  
Keyword(s):  
Computer Simulations ◽  
Molecular Basis ◽  
X Ray ◽  
X Ray Crystallography ◽  
Access Model

scholarly journals Leveraging glycomics data in glycoprotein 3D structure validation with Privateer

2020 ◽  
Author(s):  
Haroldas Bagdonas ◽  
Daniel Ungar ◽  
Jon Agirre
Keyword(s):  
Structural Biology ◽  
Large Scale ◽  
3D Structure ◽  
Structure Validation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Glycosidic Bonds ◽  
Cryo Electron Microscopy ◽  
Structure Solution ◽  
Solution Methods

The heterogeneity, mobility and complexity of glycans in glycoproteins have been, and currently remain, significant challenges in structural biology. Those aspects present unique problems to the two most prolific techniques: X-ray crystallography and cryo-electron microscopy. At the same time, advances in mass spectrometry have made it possible to get deeper insights on precisely the information that is most difficult to recover by structure solution methods: full-length glycan composition, including linkage details for the glycosidic bonds. These developments have given rise to glycomics. Thankfully, several large scale glycomics initiatives have stored results in publicly-available databases, some of which can be accessed through API interfaces. In the present work, we will describe how the Privateer carbohydrate structure validation software has been extended to harness results from glycomics projects, and its use to greatly improve the validation of 3D glycoprotein structures.

scholarly journals Cover art

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Rakesh Gudimella
Keyword(s):  
Large Scale ◽  
Molecular Model ◽  
Essential Medicines ◽  
Chemical Formula ◽  
X Ray Diffraction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Chemical Structures ◽  
Diffraction Patterns ◽  
Cover Art

Cover art by Rakesh Gudimella. In 1964, Dorothy Hodgkin won the Nobel Prize for the discovery of the structure of penicillin using the emerging technique of x-ray crystallography. The original x-ray diffraction patterns and the subsequent molecular model she created is shown in the foreground. Although the chemical formula of penicillin was known, its structure was not, making it difficult to produce on a large scale. Her discovery set us on the path to understanding antibiotic mechanisms and opened the door for the synthesis of cephalosporins and other important medications. The background shows the chemical structures of several lifesaving and influential drugs on the WHO List of Essential Medicines.

scholarly journals Biological Activity Profiles of Multitarget Ligands from X-ray Structures

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 794
Author(s):  
Christian Feldmann ◽  
Jürgen Bajorath
Keyword(s):  
Large Scale ◽  
Pharmaceutical Research ◽  
Data Consistency ◽  
Exploratory Research ◽  
Activity Data ◽  
X Ray ◽  
X Ray Crystallography ◽  
Large Scale Analysis ◽  
Compound Promiscuity ◽  
Different Sources

In pharmaceutical research, compounds with multitarget activity receive increasing attention. Such promiscuous chemical entities are prime candidates for polypharmacology, but also prone to causing undesired side effects. In addition, understanding the molecular basis and magnitude of multitarget activity is a stimulating topic for exploratory research. Computationally, compound promiscuity can be estimated through large-scale analysis of activity data. To these ends, it is critically important to take data confidence criteria and data consistency across different sources into consideration. Especially the consistency aspect has thus far only been little investigated. Therefore, we have systematically determined activity annotations and profiles of known multitarget ligands (MTLs) on the basis of activity data from different sources. All MTLs used were confirmed by X-ray crystallography of complexes with multiple targets. One of the key questions underlying our analysis has been how MTLs act in biological screens. The results of our analysis revealed significant variations of MTL activity profiles originating from different data sources. Such variations must be carefully considered in promiscuity analysis. Our study raises awareness of these issues and provides guidance for large-scale activity data analysis.

scholarly journals Covering complete proteomes with X-ray structures: a current snapshot

2014 ◽  
Vol 70 (11) ◽  
pp. 2781-2793 ◽  
Author(s):  
Marcin J. Mizianty ◽  
Xiao Fan ◽  
Jing Yan ◽  
Eric Chalmers ◽  
Christopher Woloschuk ◽  
...  
Keyword(s):  
Homology Modeling ◽  
Structure Determination ◽  
Large Scale ◽  
Structural Model ◽  
Target Selection ◽  
Three Dimensional ◽  
X Ray ◽  
X Ray Crystallography ◽  
Knowledge Based ◽  
Wide Range

Structural genomics programs have developed and applied structure-determination pipelines to a wide range of protein targets, facilitating the visualization of macromolecular interactions and the understanding of their molecular and biochemical functions. The fundamental question of whether three-dimensional structures of all proteins and all functional annotations can be determined using X-ray crystallography is investigated. A first-of-its-kind large-scale analysis of crystallization propensity for all proteins encoded in 1953 fully sequenced genomes was performed. It is shown that current X-ray crystallographic knowhow combined with homology modeling can provide structures for 25% of modeling families (protein clusters for which structural models can be obtained through homology modeling), with at least one structural model produced for each Gene Ontology functional annotation. The coverage varies between superkingdoms, with 19% for eukaryotes, 35% for bacteria and 49% for archaea, and with those of viruses following the coverage values of their hosts. It is shown that the crystallization propensities of proteomes from the taxonomic superkingdoms are distinct. The use of knowledge-based target selection is shown to substantially increase the ability to produce X-ray structures. It is demonstrated that the human proteome has one of the highest attainable coverage values among eukaryotes, and GPCR membrane proteins suitable for X-ray structure determination were determined.

scholarly journals Neuropilin-1 is a host factor for SARS-CoV-2 infection

Science ◽  
2020 ◽  
Vol 370 (6518) ◽  
pp. 861-865 ◽  
Author(s):  
James L. Daly ◽  
Boris Simonetti ◽  
Katja Klein ◽  
Kai-En Chen ◽  
Maia Kavanagh Williamson ◽  
...  
Keyword(s):  
Cell Culture ◽  
Rna Interference ◽  
Cell Attachment ◽  
Host Factor ◽  
Terminal Sequence ◽  
X Ray ◽  
X Ray Crystallography ◽  
Neuropilin 1 ◽  
Host Cell Attachment ◽  
Carboxyl Terminal

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors. We used x-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction by RNA interference or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19.

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