QRB Discovery最新文献_第10页

Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists. 预测了完全激活的人苦味受体TAS2R4与G蛋白和激动剂络合的结构。

QRB Discovery Pub Date : 2021-01-01 DOI: 10.1017/qrd.2021.1

Moon Young Yang, Amirhossein Mafi, Soo-Kyung Kim, William A Goddard, Brian Guthrie

{"title":"Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.","authors":"Moon Young Yang, Amirhossein Mafi, Soo-Kyung Kim, William A Goddard, Brian Guthrie","doi":"10.1017/qrd.2021.1","DOIUrl":"https://doi.org/10.1017/qrd.2021.1","url":null,"abstract":"Bitter taste is sensed by bitter taste receptors (TAS2Rs) that belong to the G protein-coupled receptor (GPCR) superfamily. In addition to bitter taste perception, TAS2Rs have been reported recently to be expressed in many extraoral tissues and are now known to be involved in health and disease. Despite important roles of TAS2Rs in biological functions and diseases, no crystal structure is available to help understand the signal transduction mechanism or to help develop selective ligands as new therapeutic targets. We report here the three-dimensional structure of the fully activated TAS2R4 human bitter taste receptor predicted using the GEnSeMBLE complete sampling method. This TAS2R4 structure is coupled to the gustducin G protein and to each of several agonists. We find that the G protein couples to TAS2R4 by forming strong salt bridges to each of the three intracellular loops, orienting the activated Gα5 helix of the Gα subunit to interact extensively with the cytoplasmic region of the activated receptor. We find that the TAS2Rs exhibit unique motifs distinct from typical Class A GPCRs, leading to a distinct activation mechanism and a less stable inactive state. This fully activated bitter taste receptor complex structure provides insight into the signal transduction mechanism and into ligand binding to TAS2Rs.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"2 ","pages":"e3"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2021.1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9926488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

A 3.4-Å cryo-electron microscopy structure of the human coronavirus spike trimer computationally derived from vitrified NL63 virus particles. 从玻璃化NL63病毒颗粒计算得出的人类冠状病毒刺突三聚体的3.4Å冷冻电子显微镜结构。

QRB Discovery Pub Date : 2020-11-17 DOI: 10.1017/qrd.2020.16

Kaiming Zhang, Shanshan Li, Grigore Pintilie, David Chmielewski, Michael F Schmid, Graham Simmons, Jing Jin, Wah Chiu

{"title":"A 3.4-Å cryo-electron microscopy structure of the human coronavirus spike trimer computationally derived from vitrified NL63 virus particles.","authors":"Kaiming Zhang, Shanshan Li, Grigore Pintilie, David Chmielewski, Michael F Schmid, Graham Simmons, Jing Jin, Wah Chiu","doi":"10.1017/qrd.2020.16","DOIUrl":"10.1017/qrd.2020.16","url":null,"abstract":"Human coronavirus NL63 (HCoV-NL63) is an enveloped pathogen of the family Coronaviridae that spreads worldwide and causes up to 10% of all annual respiratory diseases. HCoV-NL63 is typically associated with mild upper respiratory symptoms in children, elderly and immunocompromised individuals. It has also been shown to cause severe lower respiratory illness. NL63 shares ACE2 as a receptor for viral entry with SARS-CoV-1 and SARS-CoV-2. Here, we present the in situ structure of HCoV-NL63 spike (S) trimer at 3.4-Å resolution by single-particle cryo-EM imaging of vitrified virions without chemical fixative. It is structurally homologous to that obtained previously from the biochemically purified ectodomain of HCoV-NL63 S trimer, which displays a three-fold symmetric trimer in a single conformation. In addition to previously proposed and observed glycosylation sites, our map shows density at other sites, as well as different glycan structures. The domain arrangement within a protomer is strikingly different from that of the SARS-CoV-2 S and may explain their different requirements for activating binding to the receptor. This structure provides the basis for future studies of spike proteins with receptors, antibodies or drugs, in the native state of the coronavirus particles.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"1 ","pages":"e11"},"PeriodicalIF":0.0,"publicationDate":"2020-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10138338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biovacc-19: A Candidate Vaccine for Covid-19 (SARS-CoV-2) Developed from Analysis of its General Method of Action for Infectivity. 从对传染性一般作用方法的分析中研制出一种新冠肺炎(SARS-CoV-2)候选疫苗

QRB Discovery Pub Date : 2020-06-02 eCollection Date: 2020-01-01 DOI: 10.1017/qrd.2020.8

Birger Sørensen, Andres Susrud, Angus George Dalgleish

{"title":"Biovacc-19: A Candidate Vaccine for Covid-19 (SARS-CoV-2) Developed from Analysis of its General Method of Action for Infectivity.","authors":"Birger Sørensen, Andres Susrud, Angus George Dalgleish","doi":"10.1017/qrd.2020.8","DOIUrl":"https://doi.org/10.1017/qrd.2020.8","url":null,"abstract":"This study presents the background, rationale and method of action of Biovacc-19, a candidate vaccine for corona virus disease 2019 (Covid-19), now in advanced preclinical development, which has already passed the first acute toxicity testing. Unlike conventionally developed vaccines, Biovacc-19's method of operation is upon nonhuman-like (NHL) epitopes in 21.6% of the composition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)'s spike protein, which displays distinct distributed charge including the presence of a charged furin-like cleavage site. The logic of the design of the vaccine is explained, which starts with empirical analysis of the aetiology of SARS-CoV-2. Mistaken assumptions about SARS-CoV-2's aetiology risk creating ineffective or actively harmful vaccines, including the risk of antibody-dependent enhancement. Such problems in vaccine design are illustrated from past experience in the human immunodeficiency viruses domain. We propose that the dual effect general method of action of this chimeric virus's spike, including receptor binding domain, includes membrane components other than the angiotensin-converting enzyme 2 receptor, which explains clinical evidence of its infectivity and pathogenicity. We show the nonreceptor dependent phagocytic general method of action to be specifically related to cumulative charge from insertions placed on the SARS-CoV-2 spike surface in positions to bind efficiently by salt bridge formations; and from blasting the spike we display the NHL epitopes from which Biovacc-19 has been down-selected.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":" ","pages":"e6"},"PeriodicalIF":0.0,"publicationDate":"2020-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2020.8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39125272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 25

QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands. QTY代码设计的水溶性fc融合细胞因子受体与各自的配体结合。

QRB Discovery Pub Date : 2020-04-09 DOI: 10.1017/qrd.2020.4

Shilei Hao, David Jin, Shuguang Zhang, Rui Qing

{"title":"QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands.","authors":"Shilei Hao, David Jin, Shuguang Zhang, Rui Qing","doi":"10.1017/qrd.2020.4","DOIUrl":"https://doi.org/10.1017/qrd.2020.4","url":null,"abstract":"Cytokine release syndrome (CRS), or 'cytokine storm', is the leading side effect during chimeric antigen receptor (CAR)-T therapy that is potentially life-threatening. It also plays a critical role in viral infections such as Coronavirus Disease 2019 (COVID-19). Therefore, efficient removal of excessive cytokines is essential for treatment. We previously reported a novel protein modification tool called the QTY code, through which hydrophobic amino acids Leu, Ile, Val and Phe are replaced by Gln (Q), Thr (T) and Tyr (Y). Thus, the functional detergent-free equivalents of membrane proteins can be designed. Here, we report the application of the QTY code on six variants of cytokine receptors, including interleukin receptors IL4Rα and IL10Rα, chemokine receptors CCR9 and CXCR2, as well as interferon receptors IFNγR1 and IFNλR1. QTY-variant cytokine receptors exhibit physiological properties similar to those of native receptors without the presence of hydrophobic segments. The receptors were fused to the Fc region of immunoglobulin G (IgG) protein to form an antibody-like structure. These QTY code-designed Fc-fusion receptors were expressed in Escherichia coli and purified. The resulting water-soluble fusion receptors bind to their respective ligands with K d values affinity similar to isolated native receptors. Our cytokine receptor-Fc-fusion proteins potentially serve as an antibody-like decoy to dampen the excessive cytokine levels associated with CRS and COVID-19 infection.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"1 ","pages":"e4"},"PeriodicalIF":0.0,"publicationDate":"2020-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2020.4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9909376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Understanding Rad51 function is a prerequisite for progress in cancer research. 了解Rad51的功能是癌症研究取得进展的先决条件。

QRB Discovery Pub Date : 2020-01-01 DOI: 10.1017/qrd.2020.13

Bengt Nordén, Masayuki Takahashi

{"title":"Understanding Rad51 function is a prerequisite for progress in cancer research.","authors":"Bengt Nordén, Masayuki Takahashi","doi":"10.1017/qrd.2020.13","DOIUrl":"https://doi.org/10.1017/qrd.2020.13","url":null,"abstract":"The human protein Rad51 is double-edged in cancer contexts: on one hand, preventing tumourigenesis by eliminating potentially carcinogenic DNA damage and, on the other, promoting tumours by introducing new mutations. Understanding mechanistic details of Rad51 in homologous recombination (HR) and repair could facilitate design of novel methods, including CRISPR, for Rad51-targeted cancer treatment. Despite extensive research, however, we do not yet understand the mechanism of HR in sufficient detail, partly due to complexity, a large number of Rad51 protein units being involved in the exchange of long DNA segments. Another reason for lack of understanding could be that current recognition models of DNA interactions focus only on hydrogen bond-directed base pair formation. A more complete model may need to include, for example, the kinetic effects of DNA base stacking and unstacking ('longitudinal breathing'). These might explain how Rad51 can recognize sequence identity of DNA over several bases long stretches with high accuracy, despite the fact that a single base mismatch could be tolerated if we consider only the hydrogen bond energy. We here propose that certain specific hydrophobic effects, recently discovered destabilizing stacking of nucleobases, may play a central role in this context for the function of Rad51.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"1 ","pages":"e9"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2020.13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10300873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Editorial. 社论。

QRB Discovery Pub Date : 2020-01-01 DOI: 10.1017/qrd.2020.3

Bengt Norden

{"title":"Editorial.","authors":"Bengt Norden","doi":"10.1017/qrd.2020.3","DOIUrl":"https://doi.org/10.1017/qrd.2020.3","url":null,"abstract":"On the 51st anniversary of Quarterly Reviews of Biophysics (QRB) and on my 4th year as Editorin-Chief, it is with pleasure that I announce the new open access journal from Cambridge University Press will provide an outlet for exciting new discoveries in the burgeoning field of biophysics. The section called Discovery, which was tested in previous years as part of Quarterly Reviews of Biophysics (QRB), is now upgraded and relaunched as a journal on its own right. The launch of QRBDiscovery, which coincided with the annual conference of the Biophysical Society, promises those working in the field a fast, transparent way to publish cutting edge results. The focus for QRB Discovery will be on biological phenomena that can be described and analysed from a molecular angle. Biophysics applies approaches and methods traditionally used in physics and maths to study the living world, from molecules and cells right up to populations of animals and plants. This interdisciplinary approach has a huge number of applications and has the potential to address some of the biggest challenges facing our species and our planet. It is vital that discoveries with the potential to benefit society are published quickly and transparently. The field has beenmissing a dedicated place to publish ground-breaking results – ‘discoveries’ – that point towards an exciting direction, rather than presenting of a traditional comprehensive study. This is the gap QRB Discovery will seek to fill. Authors are encouraged to elaborate on the potential consequences and wider impact of their discoveries. If the research is of high quality and it is a sound result that points in an exciting direction – even if it is speculative – we will publish. This transparency is further extended by publishing open peer review reports. This will, expectantly, promote a more constructive type of review for authors but it will also contribute to the recognition of reviewers. I look forward to see what exciting research will be submitted next! QRB Discovery","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"1 ","pages":"e1"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2020.3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9921033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A New Natural Defense Against Airborne Pathogens. 一种对抗空气传播病原体的新天然防御。

QRB Discovery Pub Date : 2020-01-01 DOI: 10.1017/qrd.2020.9

David Edwards, Anthony Hickey, Richard Batycky, Lester Griel, Michael Lipp, Wes Dehaan, Robert Clarke, David Hava, Jason Perry, Brendan Laurenzi, Aidan K Curran, Brandon J Beddingfield, Chad J Roy, Tom Devlin, Robert Langer

{"title":"A New Natural Defense Against Airborne Pathogens.","authors":"David Edwards, Anthony Hickey, Richard Batycky, Lester Griel, Michael Lipp, Wes Dehaan, Robert Clarke, David Hava, Jason Perry, Brendan Laurenzi, Aidan K Curran, Brandon J Beddingfield, Chad J Roy, Tom Devlin, Robert Langer","doi":"10.1017/qrd.2020.9","DOIUrl":"https://doi.org/10.1017/qrd.2020.9","url":null,"abstract":"We propose the nasal administration of calcium-enriched physiological salts as a new hygienic intervention with possible therapeutic application as a response to the rapid and tenacious spread of COVID-19. We test the effectiveness of these salts against viral and bacterial pathogens in animals and humans. We find that aerosol administration of these salts to the airways diminishes the exhalation of the small particles that face masks fail to filter and, in the case of an influenza swine model, completely block airborne transmission of disease. In a study of 10 human volunteers (5 less than 65 years and 5 older than 65 years), we show that delivery of a nasal saline comprising calcium and sodium salts quickly (within 15 min) and durably (up to at least 6 h) diminishes exhaled particles from the human airways. Being predominantly smaller than 1 μm, these particles are below the size effectively filtered by conventional masks. The suppression of exhaled droplets by the nasal delivery of calcium-rich saline with aerosol droplet size of around 10 μm suggests the upper airways as a primary source of bioaerosol generation. The suppression effect is especially pronounced (99%) among those who exhale large numbers of particles. In our study, we found this high-particle exhalation group to correlate with advanced age. We argue for a new hygienic practice of nasal cleansing by a calcium-rich saline aerosol, to complement the washing of hands with ordinary soap, use of a face mask, and social distancing.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"1 ","pages":"e5"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2020.9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9909375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Computational Identification of Repeat-Containing Proteins and Systems. 含有重复序列的蛋白质和系统的计算鉴定。

QRB Discovery Pub Date : 2020-01-01 DOI: 10.1017/qrd.2020.14

Han Altae-Tran, Linyi Gao, Jonathan Strecker, Rhiannon K Macrae, Feng Zhang

引用次数: 1

Theory of Allosteric Regulation in Hsp70 Molecular Chaperones. Hsp70分子伴侣的变构调控理论。

QRB Discovery Pub Date : 2020-01-01 DOI: 10.1017/qrd.2020.10

Wayne A Hendrickson

引用次数: 5

Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation. 异常盐依赖性揭示了α-突触核蛋白纤维形成过程中吸引和排斥静电相互作用的相互作用。

QRB Discovery Pub Date : 2020-01-01 DOI: 10.1017/qrd.2020.7

Ricardo Gaspar, Mikael Lund, Emma Sparr, Sara Linse

{"title":"Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation.","authors":"Ricardo Gaspar, Mikael Lund, Emma Sparr, Sara Linse","doi":"10.1017/qrd.2020.7","DOIUrl":"https://doi.org/10.1017/qrd.2020.7","url":null,"abstract":"α-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson's disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such interactions were confirmed in Monte Carlo simulations of α-syn monomers interacting with surface-grafted C-terminal tails, and found to be weakened in the presence of salt. Thus, nucleation of α-syn aggregation depends critically on an attractive electrostatic component that is screened by salt to the extent that it outweighs the screening of the long-range repulsion between negatively charged monomers and negative surfaces. Interactions between the positively charged N-termini of α-syn monomers on the one hand, and the negatively C-termini of α-syn on fibrils or vesicles surfaces on the other hand, are thus critical for nucleation.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"1 ","pages":"e2"},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/qrd.2020.7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9925958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15