Nature chemical biology最新文献_第9页

Proteins dance to the tune of light 蛋白质随光起舞

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-27 DOI: 10.1038/s41589-024-01662-w

Christopher S. Waters

引用次数: 0

A direct hit 直接命中

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-24 DOI: 10.1038/s41589-024-01674-6

Grant Miura

引用次数: 0

On the quest for mescaline 寻找麦司卡林

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-24 DOI: 10.1038/s41589-024-01675-5

Francesco Zamberlan

引用次数: 0

Identifying p53-independent apoptosis 识别 p53 依赖性凋亡。

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-24 DOI: 10.1038/s41589-024-01676-4

Yiyun Song

引用次数: 0

Recording calcium concentrations 记录钙浓度

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-21 DOI: 10.1038/s41589-024-01656-8

Yuki Ito, Tetsuya Takano

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Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation 抑制 OSBP 可通过诱导部分高尔基体降解来阻止逆行运输

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-21 DOI: 10.1038/s41589-024-01653-x

Nianzhe He, Laura Depta, Cecilia Rossetti, Lucie Caramelle, Marko Cigler, Hogan P. Bryce-Rogers, Marine Michon, Oliver Rafn Dan, Joseph Hoock, Julien Barbier, Daniel Gillet, Alison Forrester, Georg E. Winter, Luca Laraia

{"title":"Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation","authors":"Nianzhe He, Laura Depta, Cecilia Rossetti, Lucie Caramelle, Marko Cigler, Hogan P. Bryce-Rogers, Marine Michon, Oliver Rafn Dan, Joseph Hoock, Julien Barbier, Daniel Gillet, Alison Forrester, Georg E. Winter, Luca Laraia","doi":"10.1038/s41589-024-01653-x","DOIUrl":"https://doi.org/10.1038/s41589-024-01653-x","url":null,"abstract":"<p>Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to structural similarities in the sterol-binding domains. We report the discovery of potent and selective inhibitors of oxysterol-binding protein (OSBP), which we term oxybipins. Sterol-containing chemical chimeras aimed at identifying new sterol-binding proteins by targeted degradation, led to a significant reduction in levels of Golgi-associated proteins. The degradation occurred in lysosomes, concomitant with changes in protein glycosylation, indicating that the degradation of Golgi proteins was a downstream effect. By establishing a sterol transport protein biophysical assay panel, we discovered that the oxybipins potently inhibited OSBP, resulting in blockage of retrograde trafficking and attenuating Shiga toxin toxicity. As the oxybipins do not target other sterol transporters and only stabilized OSBP in intact cells, we advocate their use as tools to study OSBP function and therapeutic relevance.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins AlphaFold2 在预测刚性球蛋白以外结构方面的能力和缺陷

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-21 DOI: 10.1038/s41589-024-01638-w

Vinayak Agarwal, Andrew C. McShan

{"title":"The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins","authors":"Vinayak Agarwal, Andrew C. McShan","doi":"10.1038/s41589-024-01638-w","DOIUrl":"10.1038/s41589-024-01638-w","url":null,"abstract":"Artificial intelligence-driven advances in protein structure prediction in recent years have raised the question: has the protein structure-prediction problem been solved? Here, with a focus on nonglobular proteins, we highlight the many strengths and potential weaknesses of DeepMind’s AlphaFold2 in the context of its biological and therapeutic applications. We summarize the subtleties associated with evaluation of AlphaFold2 model quality and reliability using the predicted local distance difference test (pLDDT) and predicted aligned error (PAE) values. We highlight various classes of proteins that AlphaFold2 can be applied to and the caveats involved. Concrete examples of how AlphaFold2 models can be integrated with experimental data in the form of small-angle X-ray scattering (SAXS), solution NMR, cryo-electron microscopy (cryo-EM) and X-ray diffraction are discussed. Finally, we highlight the need to move beyond structure prediction of rigid, static structural snapshots toward conformational ensembles and alternate biologically relevant states. The overarching theme is that careful consideration is due when using AlphaFold2-generated models to generate testable hypotheses and structural models, rather than treating predicted models as de facto ground truth structures. This Perspective proposes practical guidance to the application of AlphaFold2 for structure prediction of different classes of proteins including rigid globular proteins, intrinsically disordered proteins and alternative conformational states. The use of evaluation metrics to predict reliability of the resulting models and their integration with experimental data are also discussed.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

All roads lead to OSBP 条条大路通罗马

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-21 DOI: 10.1038/s41589-024-01639-9

Po-Hsun Brian Chen, Jeremy M. Baskin

引用次数: 0

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP 奥平内酯通过抑制 OSBP 破坏白血病对胆固醇转运的依赖性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-21 DOI: 10.1038/s41589-024-01614-4

Marko Cigler, Hana Imrichova, Fabian Frommelt, Lucie Caramelle, Laura Depta, Andrea Rukavina, Chrysanthi Kagiou, J. Thomas Hannich, Cristina Mayor-Ruiz, Giulio Superti-Furga, Sonja Sievers, Alison Forrester, Luca Laraia, Herbert Waldmann, Georg E. Winter

{"title":"Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP","authors":"Marko Cigler, Hana Imrichova, Fabian Frommelt, Lucie Caramelle, Laura Depta, Andrea Rukavina, Chrysanthi Kagiou, J. Thomas Hannich, Cristina Mayor-Ruiz, Giulio Superti-Furga, Sonja Sievers, Alison Forrester, Luca Laraia, Herbert Waldmann, Georg E. Winter","doi":"10.1038/s41589-024-01614-4","DOIUrl":"https://doi.org/10.1038/s41589-024-01614-4","url":null,"abstract":"<p>Metabolic alterations in cancer precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product-inspired small molecules can provide a resource of invaluable chemotypes. Here, we identify orpinolide, a synthetic withanolide analog with pronounced antileukemic properties, via orthogonal chemical screening. Through multiomics profiling and genome-scale CRISPR–Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate signaling at the endoplasmic reticulum–Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of orpinolide. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound orpinolide.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rationally seeded computational protein design of ɑ-helical barrels ɑ-螺旋桶的合理种子计算蛋白质设计

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-20 DOI: 10.1038/s41589-024-01642-0

Katherine I. Albanese, Rokas Petrenas, Fabio Pirro, Elise A. Naudin, Ufuk Borucu, William M. Dawson, D. Arne Scott, Graham. J. Leggett, Orion D. Weiner, Thomas A. A. Oliver, Derek N. Woolfson

{"title":"Rationally seeded computational protein design of ɑ-helical barrels","authors":"Katherine I. Albanese, Rokas Petrenas, Fabio Pirro, Elise A. Naudin, Ufuk Borucu, William M. Dawson, D. Arne Scott, Graham. J. Leggett, Orion D. Weiner, Thomas A. A. Oliver, Derek N. Woolfson","doi":"10.1038/s41589-024-01642-0","DOIUrl":"10.1038/s41589-024-01642-0","url":null,"abstract":"Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to design two families of α-helical barrel proteins with central channels that bind small molecules. Computational designs are seeded by the sequences and structures of defined de novo oligomeric barrel-forming peptides, and adjacent helices are connected by loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix–turn–helix–turn–helix motifs that are packed onto the barrels. Throughout these computational pipelines, residues that define open states of the barrels are maintained. This minimizes sequence sampling, accelerating the design process. For each of six targets, just two to six synthetic genes are made for expression in Escherichia coli. On average, 70% of these genes express to give soluble monomeric proteins that are fully characterized, including high-resolution structures for most targets that match the design models with high accuracy. An efficient computational pipeline starting from validated peptide assemblies has been used to design two families of α-helical barrel proteins with functionalizable channels. This rationally seeded computational protein design approach delivers soluble, monomeric proteins that match the design targets accurately and with high success rates.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41589-024-01642-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0