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Open AccessLearnt representations of proteins can be used for accurate prediction of small molecule binding sites on experimentally determined and predicted protein structures
Protein-ligand binding site prediction is a useful tool for understanding the functional behaviour and potential drug-target interactions of a novel protein of interest. However, most binding site prediction m...
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Article
Open AccessFragment library screening by X-ray crystallography and binding site analysis on thioredoxin glutathione reductase of Schistosoma mansoni
Schistosomiasis is caused by parasites of the genus Schistosoma, which infect more than 200 million people. Praziquantel (PZQ) has been the main drug for controlling schistosomiasis for over four decades, but des...
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Open AccessAuthor Correction: Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation
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Article
Open AccessGalaxy workflows for fragment-based virtual screening: a case study on the SARS-CoV-2 main protease
We present several workflows for protein-ligand docking and free energy calculation for use in the workflow management system Galaxy. The workflows are composed of several widely used open-source tools, includ...
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Article
Open AccessSAMPL7 protein-ligand challenge: A community-wide evaluation of computational methods against fragment screening and pose-prediction
A novel crystallographic fragment screening data set was generated and used in the SAMPL7 challenge for protein-ligands. The SAMPL challenges prospectively assess the predictive power of methods involved in co...
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Open AccessPublisher Correction: Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19
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Open AccessStructure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase
There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a targe...
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Article
Open AccessBispecific repurposed medicines targeting the viral and immunological arms of COVID-19
Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories s...
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Article
Open AccessExploring protein hotspots by optimized fragment pharmacophores
Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pha...
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Article
Open AccessCrystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoono...
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Article
Open AccessRapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures
Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to...
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Crowdsourcing drug discovery for pandemics
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Open AccessStructural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension
Bone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-β (TGF-β) family that control embryonic patterning, as well as tissue development and homeostasis. Loss of function mut...
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Article
Open AccessTuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation
Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, w...
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Article
Open AccessA multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density
In macromolecular crystallography, the rigorous detection of changed states (for example, ligand binding) is difficult unless signal is strong. Ambiguous (‘weak’ or ‘noisy’) density is experimentally common, s...
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Article
Open AccessFunctional and structural characterization of a novel putative cysteine protease cell wall-modifying multi-domain enzyme selected from a microbial metagenome
A current metagenomics focus is to interpret and transform collected genomic data into biological information. By combining structural, functional and genomic data we have assessed a novel bacterial protein se...
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Article
Open AccessA small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis
Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-β receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endo...
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Application of In Situ Diffraction in High-Throughput Structure Determination Platforms
Macromolecular crystallography (MX) is the most powerful technique available to structural biologists to visualize in atomic detail the macromolecular machinery of the cell. Since the emergence of structural g...
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Article
Ribosomal oxygenases are structurally conserved from prokaryotes to humans
Crystal structures of human and prokaryotic ribosomal oxygenases reported here, with and without their ribosomal protein substrates, support their assignments as hydroxylases, and provide insights into the evo...
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Article
Open AccessCrystal structures of human soluble guanylate cyclase catalytic domains: promiscuity of the dimer interface and a potential allosteric site
