Chemical Strategies for Investigation of Deubiquitinases PDF Download
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Author: Samuel D. Whedon
Publisher:
ISBN:
Category :
Languages : en
Pages : 122
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Book Description
Regulation of protein structure and function by post-translational modification is a key mechanism in cellular homeostasis. Among known modifications the small protein ubiquitin is unique in the breadth of functions it directs. Regulation of protein ubiquitylation is the function of more than 600 ligases, and ~100 deubiquitinases. Dysregulated ubiquitylation is involved in infection, inflammation, neurodegeneration, metabolic syndromes and cancer. Therapeutic intervention in these conditions benefits from characterization of substrate-specific ligases and deubiquitinases. Substrate specificity is documented among deubiquitinases, but lags behind knowledge of ligases. In the interest of characterizing specificity of cysteine protease deubiquitinases we have developed chemical methods for site-specific ubiquitylation and electrophile incorporation. We began by developing a ubiquitin-derived electrophile through installation of a C-terminal selenocysteine residue, and orthogonal oxidative conversion to dehydroalanine. Upon validation of the electrophile we expanded our substrate scope to a ubiquitylated peptide, with which we captured the deubiquitinase USP15. In order to access ubiquitylated lysine residues in protein regions inaccessible by native chemical ligation we undertook the synthesis of two selenazolidine amino acids for amber suppression. While conducting amber suppression selections we concurrently pursued semi-synthesis of p53, in order to introduce a C-terminal ubiquitin electrophile. Purification of the semi-synthetic protein proved materially intensive, prompting development of cleavable affinity handles for ligation product purification. A strategy for incorporation at glycine and incorporation at glutamine were developed. A glycine-derived biotin handle proved amenable to reduction by Zn, which furnishes a native glycine, and aromatic thiols, which formed novel site-specific conjugates at the previously modified glycine. Incorporation of a pendant flag tag at glutamine enabled immunoprecipitation followed by traceless tag removal with Zn.
Author: Samuel D. Whedon
Publisher:
ISBN:
Category :
Languages : en
Pages : 122
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Book Description
Regulation of protein structure and function by post-translational modification is a key mechanism in cellular homeostasis. Among known modifications the small protein ubiquitin is unique in the breadth of functions it directs. Regulation of protein ubiquitylation is the function of more than 600 ligases, and ~100 deubiquitinases. Dysregulated ubiquitylation is involved in infection, inflammation, neurodegeneration, metabolic syndromes and cancer. Therapeutic intervention in these conditions benefits from characterization of substrate-specific ligases and deubiquitinases. Substrate specificity is documented among deubiquitinases, but lags behind knowledge of ligases. In the interest of characterizing specificity of cysteine protease deubiquitinases we have developed chemical methods for site-specific ubiquitylation and electrophile incorporation. We began by developing a ubiquitin-derived electrophile through installation of a C-terminal selenocysteine residue, and orthogonal oxidative conversion to dehydroalanine. Upon validation of the electrophile we expanded our substrate scope to a ubiquitylated peptide, with which we captured the deubiquitinase USP15. In order to access ubiquitylated lysine residues in protein regions inaccessible by native chemical ligation we undertook the synthesis of two selenazolidine amino acids for amber suppression. While conducting amber suppression selections we concurrently pursued semi-synthesis of p53, in order to introduce a C-terminal ubiquitin electrophile. Purification of the semi-synthetic protein proved materially intensive, prompting development of cleavable affinity handles for ligation product purification. A strategy for incorporation at glycine and incorporation at glutamine were developed. A glycine-derived biotin handle proved amenable to reduction by Zn, which furnishes a native glycine, and aromatic thiols, which formed novel site-specific conjugates at the previously modified glycine. Incorporation of a pendant flag tag at glutamine enabled immunoprecipitation followed by traceless tag removal with Zn.
Author:
Publisher: Elsevier
ISBN: 0081026919
Category : Science
Languages : en
Pages : 4266
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Book Description
Comprehensive Natural Products III, Third Edition, Seven Volume Set updates and complements the previous two editions, including recent advances in cofactor chemistry, structural diversity of natural products and secondary metabolites, enzymes and enzyme mechanisms and new bioinformatics tools. Natural products research is a dynamic discipline at the intersection of chemistry and biology concerned with isolation, identification, structure elucidation, and chemical characteristics of naturally occurring compounds such as pheromones, carbohydrates, nucleic acids and enzymes. This book reviews the accumulated efforts of chemical and biological research to understand living organisms and their distinctive effects on health and medicine and to stimulate new ideas among the established natural products community. Provides readers with an in-depth review of current natural products research and a critical insight into the future direction of the field Bridges the gap in knowledge by covering developments in the field since the second edition published in 2010 Split into 7 sections on key topics to allow students, researchers and professionals to find relevant information quickly and easily Ensures that the knowledge within is easily understood by and applicable to a large audience
Author: Benjamin F. Cravatt
Publisher: Springer
ISBN: 3030111431
Category : Medical
Languages : en
Pages : 417
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Book Description
This volume provides a collection of contemporary perspectives on using activity-based protein profiling (ABPP) for biological discoveries in protein science, microbiology, and immunology. A common theme throughout is the special utility of ABPP to interrogate protein function and small-molecule interactions on a global scale in native biological systems. Each chapter showcases distinct advantages of ABPP applied to diverse protein classes and biological systems. As such, the book offers readers valuable insights into the basic principles of ABPP technology and how to apply this approach to biological questions ranging from the study of post-translational modifications to targeting bacterial effectors in host-pathogen interactions.
Author: Steven Howard
Publisher: Royal Society of Chemistry
ISBN: 1782625658
Category : Medical
Languages : en
Pages : 314
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Book Description
Fragment-based drug discovery is a rapidly evolving area of research, which has recently seen new applications in areas such as epigenetics, GPCRs and the identification of novel allosteric binding pockets. The first fragment-derived drug was recently approved for the treatment of melanoma. It is hoped that this approval is just the beginning of the many drugs yet to be discovered using this fascinating technique. This book is written from a Chemist's perspective and comprehensively assesses the impact of fragment-based drug discovery on a wide variety of areas of medicinal chemistry. It will prove to be an invaluable resource for medicinal chemists working in academia and industry, as well as anyone interested in novel drug discovery techniques.
Author: Huib Ovaa
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.
Author: Gerard Drewes
Publisher: Humana Press
ISBN: 9781617793639
Category : Science
Languages : en
Pages : 0
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Book Description
The multidisciplinary science of chemical proteomics studies how small molecules of synthetic or natural origin bind to proteins and modulate their function. In Chemical Proteomics: Methods and Protocols, expert researchers in the field provide key techniques to investigate chemical proteomics focusing on analytical strategies, how probes are generated, techniques for the discovery of small molecule targets and the probing of target function, and small molecule ligand and drug discovery. Written in the highly successful Methods in Molecular BiologyTM series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and key tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Chemical Proteomics : Methods and Protocols seeks to provide methodologies that will contribute to a wider application of chemical proteomics methods in biochemical and cell biological laboratories.
Author: Julian Adams
Publisher: Springer Science & Business Media
ISBN: 1592597947
Category : Medical
Languages : en
Pages : 319
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Book Description
A panel of leading academic and pharmaceutical investigators takes stock of the remarkable work that has been accomplished to date with proteasome inhibitors in cancer, and examines emerging therapeutic possibilities. The topics range from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of current clinical trials underway. The discussion of rationales for testing proteasome inhibitors in cancer models covers the role of the proteasome in NF-kB activation, the combining of conventional chemotherapy and radiation with proteasome inhibition, notably PS-341, new proteasome methods of inhibiting viral maturation, and the role of protesome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (VelcadeTM) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.
Author: Benjamin Preiss
Publisher: Elsevier
ISBN: 0323155146
Category : Nature
Languages : en
Pages : 343
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Book Description
Regulation of HMG-CoA Reductase is a nine-chapter text that focuses on the research developments in the regulation of HMG-CoA reductase enzyme and cholesterol biosynthesis. This book deals first with the role of cholesterol in the regulation of its own biosynthesis and the work involving compactin and related competitive inhibitors of HMG-CoA reductase. The subsequent chapters examine the reversible phosphorylation of HMG-CoA reductase in hormonal and other short-term physiological changes and the structure and properties of the enzyme, including evidence for modulation of enzyme activity and structure unrelated to phosphorylation. These topics are followed by discussions on the regulation of reductase in the biosynthesis of ubiquinone, dolichols, and isopentenyl-tRNA and the regulation of reductase activity in extrahepatic tissues. This text further explores the contributions made through the use of cultured cells and their genetic manipulation, with emphasis on the great potential of this approach. The concluding chapters address the status of the low-density lipoprotein pathway and related mechanisms. These chapters also consider the regulation of human hepatic HMG-CoA reductase and the special problems inherent in work with human tissues. Enzyme scientists and researchers and graduate students will find this book invaluable.
Author: Charles W. Carter
Publisher: Gulf Professional Publishing
ISBN: 9780121827779
Category : Computer simulation
Languages : en
Pages : 756
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Book Description
Annotation Accurate molecular structures is vital for rational drug design and for structure based functional studies directed toward the development of effective therapeutic agents and drugs. Crystallography can reliably predict structure, both in terms of folding and atomic details of bonding. * Phases * Map interpretation and refinement * Analysis and software.
Author: Hilmar Weinmann
Publisher: Royal Society of Chemistry
ISBN: 1839160772
Category : Medical
Languages : en
Pages : 382
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Book Description
Targeting protein degradation using small molecules is one of the most exciting small-molecule therapeutic strategies in decades and a rapidly growing area of research. In particular, the development of proteolysis targeting chimera (PROTACs) as potential drugs capable of recruiting target proteins to the cellular quality control machinery for elimination has opened new avenues to address traditionally ‘difficult to target’ proteins. This book provides a comprehensive overview from the leading academic and industrial experts on recent developments, scope and limitations in this dynamically growing research area; an ideal reference work for researchers in drug discovery and chemical biology as well as advanced students.
