The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo–electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom 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. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease 2019 (COVID-19), with over 84.66 million infections and 1.83 million deaths as reported on 3 January 2021 (refs. 1,2). SARS-CoV-2 is a positive-sense, single-stranded RNA virus. SARS-CoV-2 and several related beta-coronaviruses, including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), are highly pathogenic. Infections can lead to severe acute respiratory syndrome, loss of lung function and, in severe cases, death. Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 has a higher capacity of human-to-human infections, which resulted in the rapidly growing pandemic 3. Finding an effective treatment for COVID-19, potentially also through drug repurposing, is an urgent but unmet medical need. Suramin (Fig. 1a) is a century-old drug that has been used to treat African sleeping sickness and river blindness 4,5. It has also been shown to be effective in inhibiting the replication of a wide range of viruses, including enteroviruses 6 , Zika virus 7 , Chikungunya 8 and Ebola viruses 9. The viral inhibition mechanisms of suramin are diverse, including inhibition of viral attachment, viral entry and release from host cells in part through interactions with viral capsid proteins 7,8,10,11. Recently, suramin has been shown to inhibit SARS-CoV-2 infection in cell culture by preventing cellular entry of the virus 12. Here we report that suramin is also a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), an essential enzyme for the viral life cycle. The potency of suramin in biochemical RdRp inhibition assays is at least 20-fold more potent than remdesivir, the current Food and Drug Administration-approved nucleotide drug for the treatment of COVID-19. The activity of suramin in cell-based viral inhibition is similar to remdesivir because the highly negative charge of suramin prevents efficient cellular uptake. A cryogenic electron microscopy (cryo-EM) structure reveals that suramin binds to the RdRp active site, blocking the binding of both RNA template and primer strands. These results provide a structural template for the design of next generation suramin derivatives as SARS-CoV-2 RdRp inhibitors. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin Wanchao Yin 1,

In this study, a flexible asymmetrical all-solid-state supercapacitor with high electrochemical performance was fabricated with Ni/MnO2-filter paper (FP) as the positive electrode and Ni/active carbon (AC)-filter paper as negative electrode, separated with poly(vinyl alcohol) (PVA)-Na2SO4 electrolyte. A simple procedure, such as electroless plating, was introduced to prepare the Ni/MnO2-FP electrode on the conventional laboratory FP, combined with the subsequent step of electrodeposition. Electrochemical results show that the as-prepared electrodes display outstanding areal specific capacitance (1900 mF/cm(2) at 5 mV/s) and excellent cycling performance (85.1% retention after 1000 cycles at 20 mA/cm(2)). Such a flexible supercapacitor assembled asymmetrically in the solid state exhibits a large volume energy density (0.78 mWh/cm(3)) and superior flexibility under different bending conditions. It has been demonstrated that the supercapacitors could be used as a power source to drive a 3 V light-emitting diode indicator. This study may provide an available method for designing and fabricating flexible supercapacitors with high performance in the application of wearable and portable electronics based on easily available materials.

BackgroundLeucine-rich repeat receptor-like kinases (LRR-RLKs) constitute the largest subfamily of receptor-like kinases in plant. A number of reports have demonstrated that plant LRR-RLKs play important roles in growth, development, differentiation, and stress responses. However, no comprehensive analysis of this gene family has been carried out in legume species.ResultsBased on the principles of sequence similarity and domain conservation, a total of 467 LRR-RLK genes were identified in soybean genome. The GmLRR-RLKs are non-randomly distributed across all 20 chromosomes of soybean and about 73.3 % of them are located in segmental duplicated regions. The analysis of synonymous substitutions for putative paralogous gene pairs indicated that most of these gene pairs resulted from segmental duplications in soybean genome. Furthermore, the exon/intron organization, motif composition and arrangements were considerably conserved among members of the same groups or subgroups in the constructed phylogenetic tree. The close phylogenetic relationship between soybean LRR-RLK genes with identified Arabidopsis genes in the same group also provided insight into their putative functions. Expression profiling analysis of GmLRR-RLKs suggested that they appeared to be differentially expressed among different tissues and some of duplicated genes exhibited divergent expression patterns. In addition, artificial selected GmLRR-RLKs were also identified by comparing the SNPs between wild and cultivated soybeans and 17 genes were detected in regions previously reported to contain domestication-related QTLs.ConclusionsComprehensive and evolutionary analysis of soybean LRR-RLK gene family was performed at whole genome level. The data provides valuable tools in future efforts to identify functional divergence of this gene family and gene diversity among different genotypes in legume species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-016-0744-1) contains supplementary material, which is available to authorized users.

Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn’s disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a Gs heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.

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Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 Å. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the α-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine.

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