A core epitope targeting antibody of SARS-CoV-2

Dear Editor,Tremendous efforts have been made globally to develop therapeutics and prophylactics against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)which has caused thousands of millions of infections and deaths worldwide.A series of potent neutralizing antibodies with defined epitopes targeting RBD have been recently identified with different strategies.However,being an RNA virus,the instability of the SARS-CoV-2 genome results in numerous S-protein variants with altered viral phenotypes.

G protein-coupled receptors: structure- and function-based drug discovery

As one of the most successful therapeutic target families,G protein-coupled receptors(GPCRs)have experienced a transformation from random ligand screening to knowledge-driven drug design.We are eye-witnessing tremendous progresses made recently in the understanding of their structure-function relationships that facilitated drug development at an unprecedented pace.This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.

The proline synthesis enzyme P5CS forms cytoophidia in Drosophila

Compartmentation of enzymes via filamentation has arisen as a mechanism for the regulation of metabolism.In 2010,three groups independently reported that CTP synthase(CTPS)can assemble into a filamentous structure termed the cytoophidium.In searching for CTPS-interacting proteins,here we perform a yeast two-hybrid screening of Drosophila proteins and identify a putative CTPS-interacting protein,△~1-pyrroline-5-carboxylate synthase(P5CS).Using the Drosophila follicle cell as the in vivo model,we confirm that P5CS forms cytoophidia,which are associated with CTPS cytoophidia.Overexpression of P5CS increases the length of CTPS cytoophidia.Conversely,filamentation of CTPS affects the morphology of P5CS cytoophid ia.Finally,in vitro analyses confirm the filament-fo rming property of P5CS.Our work links CTPS with P5CS,two enzymes involved in the rate-limiting steps in pyrimidine and proline biosynthesis,respectively.

Building the Chordata Olfactory Receptor Database using more than 400,000 receptors annotated by Genome2OR

Olfactory receptors are poorly annotated for most genome-sequenced chordates.To address this deficiency,we developed a nhmmer-based olfactory receptor annotation tool Genome2OR(https://github.com/To Hanwei/Genome2OR.git),and used it to process 1,695 sequenced chordate genomes in the NCBI Assembly database as of January,2021.In total,765,248 olfactory receptor genes were annotated,with 404,426 functional genes and 360,822 pseudogenes,which represents a four-fold increase in the number of annotated olfactory receptors.Based on the annotation data,we built a database called Chordata Olfactory Receptor Database(CORD,https://cord.ihuman.shanghaitech.edu.cn)for archiving,analysing and disseminating the data.Beyond the primary data,we offer derivative information,including pictures of species,cross references to public databases,structural models,sequence similarity networks and sequence profiles in the CORD.Furthermore,we did brief analyses on these receptors,including building a huge protein sequence similarity network covering all receptors in the database,and clustering them into 20 communities,classifying the 20 communities into three categories based on their presences/absences in ray-finned fish and/or lobe-finned fish.We infer that olfactory receptors should have unique activation and desensitization mechanisms by analysing their sequences and structural models.We believe the CORD can benefit the researchers and the general public who are interested in olfaction.

Inactivity of YGL082W in vitro due to impairment of conformational change in the catalytic center loop

MINDY-1 is a recently discovered new family of deubiquitinating enzymes(DUB),but one of its yeast homologs,YGL082 W,does not show any DUB activity in vitro.Sequence alignment shows that YGL082 W possesses the correct catalytic triad,and yet did not catalyze either the hydrolysis of di-ubiquitin,crosslinking with C-terminally propargylated ubiquitin,or hydrolysis of ubiquitin-7-amino-4-methylcoumarin.After obtaining a crystal structure of the catalytic domain of YGL082 W,we identified an interesting difference between the catalytic center loop of YGL082 W and that of its human homolog MINDY-1.Because the conformation of the catalytic center loop was previously reported to be important for the deubiquitination activity of MINDY-1,we hypothesized that Glu27(instead of the corresponding Pro136 in MINDY-1) of the catalytic center loop of YGL082 W may impair the conformational change and account for the lack of activity.This hypothesis was supported by homology modeling and molecular dynamics simulations,which showed that the Pro-to-Glu mutation(P136 E mutation for MINDY-1) creates a hydrogen bond that inhibits the conformation change of the catalytic center loop of MINDY-1.Further experiments through site-directed mutation validated this hypothesis,showing that the P27 E mutation caused MIY1(a homologous active DUB from yeast) to lose activity.