Chemistry & biology最新文献_第7页

An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors. PNU-120596在α - 7烟碱乙酰胆碱受体中的一个不变的正构位和远程变构相互作用网络。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-07-23 DOI: 10.1016/j.chembiol.2015.06.018

Christopher B Marotta, Henry A Lester, Dennis A Dougherty

{"title":"An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors.","authors":"Christopher B Marotta, Henry A Lester, Dennis A Dougherty","doi":"10.1016/j.chembiol.2015.06.018","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.018","url":null,"abstract":"Nicotinic acetylcholine receptors (nAChRs) are vital to neuronal signaling, are implicated in important processes such as learning and memory, and are therapeutic targets for neural diseases. The α7 nAChR has been implicated in Alzheimer's disease and schizophrenia, and allosteric modulators have become one focus of drug development efforts. We investigate the mode of action of the α7-selective positive allosteric modulator, PNU-120596, and show that the higher potency of acetylcholine in the presence of PNU-120596 is not due to an altered agonist binding site. In addition, we propose several residues in the gating interface and transmembrane region that are functionally important to transduction of allosteric properties, and link PNU-120596, the acetylcholine binding region, and the receptor gate. These results suggest global protein stabilization from a communication network through several key residues that alter the gating equilibrium of the receptor while leaving the agonist binding properties unperturbed. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 8","pages":"1063-73"},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33867887","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: 6

Comprehensive Structural and Biochemical Analysis of the Terminal Myxalamid Reductase Domain for the Engineered Production of Primary Alcohols. 工程生产伯醇用末端粘酰胺还原酶结构域的综合结构和生化分析。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-07-30 DOI: 10.1016/j.chembiol.2015.06.022

Jesus F Barajas, Ryan M Phelan, Andrew J Schaub, Jaclyn T Kliewer, Peter J Kelly, David R Jackson, Ray Luo, Jay D Keasling, Shiou-Chuan Tsai

{"title":"Comprehensive Structural and Biochemical Analysis of the Terminal Myxalamid Reductase Domain for the Engineered Production of Primary Alcohols.","authors":"Jesus F Barajas, Ryan M Phelan, Andrew J Schaub, Jaclyn T Kliewer, Peter J Kelly, David R Jackson, Ray Luo, Jay D Keasling, Shiou-Chuan Tsai","doi":"10.1016/j.chembiol.2015.06.022","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.022","url":null,"abstract":"The terminal reductase (R) domain from the non-ribosomal peptide synthetase (NRPS) module MxaA in Stigmatella aurantiaca Sga15 catalyzes a non-processive four-electron reduction to produce the myxalamide family of secondary metabolites. Despite widespread use in nature, a lack of structural and mechanistic information concerning reductive release from polyketide synthase (PKS) and NRPS assembly lines principally limits our ability to redesign R domains with altered or improved activity. Here we report crystal structures for MxaA R, both in the absence and, for the first time, in the presence of the NADPH cofactor. Molecular dynamics simulations were employed to provide a deeper understanding of this domain and further identify residues critical for structural integrity, substrate binding, and catalysis. Aggregate computational and structural findings provided a basis for mechanistic investigations and, in the process, delivered a rationally altered variant with improved activity toward highly reduced substrates. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 8","pages":"1018-29"},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33888273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 48

Design and Synthesis of Activity-Based Probes and Inhibitors for Bleomycin Hydrolase. 博莱霉素水解酶活性探针及抑制剂的设计与合成。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-08-06 DOI: 10.1016/j.chembiol.2015.07.010

Wouter A van der Linden, Ehud Segal, Matthew A Child, Anna Byzia, Marcin Drąg, Matthew Bogyo

{"title":"Design and Synthesis of Activity-Based Probes and Inhibitors for Bleomycin Hydrolase.","authors":"Wouter A van der Linden, Ehud Segal, Matthew A Child, Anna Byzia, Marcin Drąg, Matthew Bogyo","doi":"10.1016/j.chembiol.2015.07.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.07.010","url":null,"abstract":"Bleomycin hydrolase (BLMH) is a neutral cysteine aminopeptidase that has been ascribed roles in many physiological and pathological processes, yet its primary biological function remains enigmatic. In this work, we describe the results of screening of a library of fluorogenic substrates to identify non-natural amino acids that are optimally recognized by BLMH. This screen identified several substrates with kcat/KM values that are substantially improved over the previously reported fluorogenic substrates for this enzyme. The substrate sequences were used to design activity-based probes that showed potent labeling of recombinant BLMH as well as endogenously expressed BLMH in cell extracts, and in intact cells. Importantly, we identify potent BLMH inhibitors that are able to fully inhibit endogenous BLMH activity in intact cells. These probes and inhibitors will be valuable new reagents to study BLMH function in cellular and animal models of human diseases where BLMH is likely to be involved. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 8","pages":"995-1001"},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33905812","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: 7

Remodeling Amyloid Fibers: Baker's Yeast Shows Us the Way. 重塑淀粉样纤维:面包师酵母为我们指明了道路。

Chemistry & biology Pub Date : 2015-08-20 DOI: 10.1016/j.chembiol.2015.08.001

Eva Asp, Ming Proschitsky, Rajaraman Krishnan

引用次数: 0

New Griselimycins for Treatment of Tuberculosis. 治疗结核病的新型稻谷霉素。

Chemistry & biology Pub Date : 2015-08-20 DOI: 10.1016/j.chembiol.2015.08.002

Ulrike Holzgrabe

引用次数: 13

Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors. 内源性酰基辅酶a辅助因子对组蛋白乙酰转移酶的代谢调节。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-07-16 DOI: 10.1016/j.chembiol.2015.06.015

David C Montgomery, Alexander W Sorum, Laura Guasch, Marc C Nicklaus, Jordan L Meier

{"title":"Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors.","authors":"David C Montgomery, Alexander W Sorum, Laura Guasch, Marc C Nicklaus, Jordan L Meier","doi":"10.1016/j.chembiol.2015.06.015","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.015","url":null,"abstract":"The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 8","pages":"1030-1039"},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34299772","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: 51

Thiopeptide Antibiotics Exhibit a Dual Mode of Action against Intracellular Pathogens by Affecting Both Host and Microbe. 硫肽抗生素通过影响宿主和微生物对细胞内病原体表现出双重作用模式。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-07-23 DOI: 10.1016/j.chembiol.2015.06.019

Qingfei Zheng, Qinglan Wang, Shoufeng Wang, Jiequn Wu, Qian Gao, Wen Liu

引用次数: 57

Chemical Lectinology: Tools for Probing the Ligands and Dynamics of Mammalian Lectins In Vivo. 化学凝集学:探究哺乳动物体内凝集素配体和动力学的工具。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-08-06 DOI: 10.1016/j.chembiol.2015.07.009

Brian Belardi, Carolyn R Bertozzi

{"title":"Chemical Lectinology: Tools for Probing the Ligands and Dynamics of Mammalian Lectins In Vivo.","authors":"Brian Belardi, Carolyn R Bertozzi","doi":"10.1016/j.chembiol.2015.07.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.07.009","url":null,"abstract":"The importance and complexity associated with the totality of glycan structures, i.e. the glycome, has garnered significant attention from chemists and biologists alike. However, what is lacking from this biochemical picture is how cells, tissues, and organisms interpret glycan patterns and translate this information into appropriate responses. Lectins, glycan-binding proteins, are thought to bridge this gap by decoding the glycome and dictating cell fate based on the underlying chemical identities and properties of the glycome. Yet, our understanding of the in vivo ligands and function for most lectins is still incomplete. This review focuses on recent advances in chemical tools to study the specificity and dynamics of mammalian lectins in live cells. A picture emerges of lectin function that is highly sensitive to its organization, which in turn drastically shapes immunity and cancer progression. We hope this review will inspire biologists to make use of these new techniques and stimulate chemists to continue developing innovative approaches to probe lectin biology in vivo. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 8","pages":"983-93"},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33905811","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: 21

Systems Analysis of Protein Fatty Acylation in Herpes Simplex Virus-Infected Cells Using Chemical Proteomics. 单纯疱疹病毒感染细胞中蛋白质脂肪酰化的化学蛋白质组学系统分析。

Chemistry & biology Pub Date : 2015-08-20 Epub Date: 2015-08-06 DOI: 10.1016/j.chembiol.2015.06.024

Remigiusz A Serwa, Fernando Abaitua, Eberhard Krause, Edward W Tate, Peter O'Hare

{"title":"Systems Analysis of Protein Fatty Acylation in Herpes Simplex Virus-Infected Cells Using Chemical Proteomics.","authors":"Remigiusz A Serwa, Fernando Abaitua, Eberhard Krause, Edward W Tate, Peter O'Hare","doi":"10.1016/j.chembiol.2015.06.024","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.024","url":null,"abstract":"Protein fatty acylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Acylation also modulates the function and localization of virus-encoded proteins. Here, we employ chemical proteomics tools, bio-orthogonal probes, and capture reagents to study myristoylation and palmitoylation during infection with herpes simplex virus (HSV). Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed. Furthermore, we found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Taken together, our results provide broad oversight of protein acylation during HSV infection, a roadmap for similar analysis in other systems, and a resource with which to pursue specific analysis of systems and functions. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 8","pages":"1008-17"},"PeriodicalIF":0.0,"publicationDate":"2015-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33905809","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: 48

Site-Specific Proteomic Mapping Identifies Selectively Modified Regulatory Cysteine Residues in Functionally Distinct Protein Networks. 位点特异性蛋白质组学定位鉴定选择性修饰的调节半胱氨酸残基在功能不同的蛋白质网络。

Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-07-09 DOI: 10.1016/j.chembiol.2015.06.010

Neal S Gould, Perry Evans, Pablo Martínez-Acedo, Stefano M Marino, Vadim N Gladyshev, Kate S Carroll, Harry Ischiropoulos

{"title":"Site-Specific Proteomic Mapping Identifies Selectively Modified Regulatory Cysteine Residues in Functionally Distinct Protein Networks.","authors":"Neal S Gould, Perry Evans, Pablo Martínez-Acedo, Stefano M Marino, Vadim N Gladyshev, Kate S Carroll, Harry Ischiropoulos","doi":"10.1016/j.chembiol.2015.06.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.010","url":null,"abstract":"S-Acylation, S-glutathionylation, S-nitrosylation, and S-sulfenylation are prominent, chemically distinct modifications that regulate protein function, redox sensing, and trafficking. Although the biological significance of these modifications is increasingly appreciated, their integration in the proteome remains unknown. Novel mass spectrometry-based technologies identified 2,596 predominately unique sites in 1,319 mouse liver proteins under physiological conditions. Structural analysis localized the modifications in unique, evolutionary conserved protein segments, outside commonly annotated functional regions. Contrary to expectations, propensity for modification did not correlate with biophysical properties that regulate cysteine reactivity. However, the in vivo chemical reactivity is fine-tuned for specificity, demonstrated by the nominal complementation between the four modifications and quantitative proteomics which showed that a reduction in S-nitrosylation is not correlated with increased S-glutathionylation. A comprehensive survey uncovered clustering of modifications within biologically related protein networks. The data provide the first evidence for the occurrence of distinct, endogenous protein networks that undergo redox signaling through specific cysteine modifications.","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"965-75"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34280756","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: 108