scholarly journals Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer

2021 ◽  
Author(s):  
Erinna F. Lee ◽  
W. Douglas Fairlie
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Basic Science ◽  
Great Success ◽  
Protein Protein Interactions ◽  
New Class ◽  
Success Stories ◽  
History Of ◽  
Approved Drugs ◽  
Close Relatives

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.

Structural biology of plant sulfur metabolism: from sulfate to glutathione

2019 ◽  
Vol 70 (16) ◽  
pp. 4089-4103 ◽  
Author(s):  
Joseph M Jez
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Sulfur Metabolism ◽  
Essential Element ◽  
Glutathione Synthetase ◽  
Protein Protein Interactions ◽  
Glutathione Biosynthesis ◽  
Wide Range ◽  
Aps Reductase ◽  
Level Information

Abstract Sulfur is an essential element for all organisms. Plants must assimilate this nutrient from the environment and convert it into metabolically useful forms for the biosynthesis of a wide range of compounds, including cysteine and glutathione. This review summarizes structural biology studies on the enzymes involved in plant sulfur assimilation [ATP sulfurylase, adenosine-5'-phosphate (APS) reductase, and sulfite reductase], cysteine biosynthesis (serine acetyltransferase and O-acetylserine sulfhydrylase), and glutathione biosynthesis (glutamate-cysteine ligase and glutathione synthetase) pathways. Overall, X-ray crystal structures of enzymes in these core pathways provide molecular-level information on the chemical events that allow plants to incorporate sulfur into essential metabolites and revealed new biochemical regulatory mechanisms, such as structural rearrangements, protein–protein interactions, and thiol-based redox switches, for controlling different steps in these pathways.

Multivalent peptides displayed on OEGMA-based copolymers for the modulation of protein–protein interactions

2015 ◽  
Vol 6 (45) ◽  
pp. 7862-7870 ◽  
Author(s):  
Yujie Li ◽  
Tao Li ◽  
Jinghui Wang ◽  
Xiaojia Bao ◽  
Yibing Zhao ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Peptide Conjugates ◽  
New Class ◽  
Multiple Copies

We report a new class of copolymer–peptide conjugates which exploits the comb-shaped pOEGMA as a polymeric backbone, into which multiple copies of peptide chains that can modulate intracellular p53–Mdm2 or p53–Mdm4 protein interactions are incorporated.

scholarly journals A Critical Review of Bottom-Up Proteomics: The Good, the Bad, and the Future of This Field

Proteomes ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 14 ◽  
Author(s):  
Emmalyn J. Dupree ◽  
Madhuri Jayathirtha ◽  
Hannah Yorkey ◽  
Marius Mihasan ◽  
Brindusa Alina Petre ◽  
...  
Keyword(s):  
Data Analysis ◽  
Sample Preparation ◽  
Protein Interactions ◽  
Clinical Setting ◽  
Critical Review ◽  
Basic Science ◽  
Protein Protein Interactions ◽  
Bottom Up ◽  
Post Translational Modifications ◽  
The Future

Proteomics is the field of study that includes the analysis of proteins, from either a basic science prospective or a clinical one. Proteins can be investigated for their abundance, variety of proteoforms due to post-translational modifications (PTMs), and their stable or transient protein–protein interactions. This can be especially beneficial in the clinical setting when studying proteins involved in different diseases and conditions. Here, we aim to describe a bottom-up proteomics workflow from sample preparation to data analysis, including all of its benefits and pitfalls. We also describe potential improvements in this type of proteomics workflow for the future.

Structural biology and drug discovery for protein–protein interactions

2012 ◽  
Vol 33 (5) ◽  
pp. 241-248 ◽  
Author(s):  
Harry Jubb ◽  
Alicia P. Higueruelo ◽  
Anja Winter ◽  
Tom L. Blundell
Keyword(s):  
Drug Discovery ◽  
Structural Biology ◽  
Protein Interactions ◽  
Protein Protein Interactions

scholarly journals The structural evolution of host-pathogen protein interactions: an integrative approach

2019 ◽  
Author(s):  
Anderson F. Brito ◽  
John W. Pinney
Keyword(s):  
Protein Interactions ◽  
Homology Modelling ◽  
Structural Evolution ◽  
Integrative Approach ◽  
Binding Affinities ◽  
Protein Protein Interactions ◽  
Host Pathogen ◽  
Cell Membrane Proteins ◽  
Pathogen Protein ◽  
History Of

ABSTRACTThe evolution of protein-protein interactions (PPIs) is directly influenced by the evolutionary histories of the genes and the species encoding the interacting proteins. When it comes to PPIs of host-pathogen systems, the complexity of their evolution is much higher, as two independent, but biologically associated entities, are involved. In this work, an integrative approach combining phylogenetics, tree reconciliations, ancestral sequence reconstructions, and homology modelling is proposed for studying the evolution of host-pathogen PPIs. As a case study, we analysed the evolution of interactions between herpesviral glycoproteins gD/gG and the cell membrane proteins nectins. By modelling the structures of more than 12,000 ancestral states of these virus-host complexes it was found that in early times of their evolution, these proteins were unable to interact, most probably due to electrostatic incompatibilities between their interfaces. After the event of gene duplication that gave rise to a paralog of gD (known as gG), both protein lineages evolved following distinct functional constraints, with most gD reaching high binding affinities towards nectins, while gG lost such ability, most probably due to a process of neofunctionalization. Based on their favourable interaction energies (negative ΔG), it is possible to hypothesize that apart from nectins 1 and 2, some alphaherpesviruses might also use nectins 3 and 4 as cell receptors. These findings show that the proposed integrative method is suitable for modelling the evolution of host-pathogen protein interactions, and useful for raising new hypotheses that broaden our understanding about the evolutionary history of PPIs, and their molecular functioning.

scholarly journals IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2184
Author(s):  
Doreen M. Floss ◽  
Jens M. Moll ◽  
Jürgen Scheller
Keyword(s):  
Protein Interactions ◽  
Intracellular Signaling ◽  
Signaling Cascades ◽  
Structural Knowledge ◽  
Nucleotide Polymorphisms ◽  
Protein Protein Interactions ◽  
Single Nucleotide ◽  
Mediated Effects ◽  
Protein Functions ◽  
Close Relatives

Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways.

Genetically encoded selective cross-linkers and emerging applications

2020 ◽  
Vol 48 (4) ◽  
pp. 1807-1817
Author(s):  
Haiyan Ren
Keyword(s):  
Protein Interactions ◽  
Unnatural Amino Acids ◽  
Protein Complexes ◽  
Living Cells ◽  
Cross Linking ◽  
Protein Protein Interactions ◽  
New Class ◽  
Selective Reaction ◽  
Biological Studies ◽  
Lower Background

There has been a large amount of interest in the development of genetically encoded cross-linkers that target functional groups naturally present in cells. Recently, a new class of unnatural amino acids that specifically react with target residues were developed and genetically incorporated. The selective reaction shows higher cross-linking efficiency, lower background and predictable cross-linking sites. It has been applied to enhance protein/peptide stability, pinpoint protein–protein interactions, stabilize protein complexes, engineer covalent protein inhibitors, identify phosphatases in living cells, etc. These new covalent linkages provide excellent new tools for protein engineering and biological studies. Their applications in biotherapy will provide considerable opportunities for innovating and improving biomolecular medicines.

scholarly journals Linkers in the structural biology of protein-protein interactions

2013 ◽  
Vol 22 (2) ◽  
pp. 153-167 ◽  
Author(s):  
Vishnu Priyanka Reddy Chichili ◽  
Veerendra Kumar ◽  
J. Sivaraman
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Protein Protein Interactions

scholarly journals Paramagnetic NMR Spectroscopy Is a Tool to Address Reactivity, Structure, and Protein–Protein Interactions of Metalloproteins: The Case of Iron–Sulfur Proteins

2020 ◽  
Vol 6 (4) ◽  
pp. 46
Author(s):  
Mario Piccioli
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Magnetic Coupling ◽  
Paramagnetic Nmr ◽  
Relaxation Rates ◽  
Protein Protein Interactions ◽  
Iron Sulfur Cluster ◽  
Protein Protein Interaction ◽  
Iron Sulfur ◽  
Protein Protein Interaction Networks

The study of cellular machineries responsible for the iron–sulfur (Fe–S) cluster biogenesis has led to the identification of a large number of proteins, whose importance for life is documented by an increasing number of diseases linked to them. The labile nature of Fe–S clusters and the transient protein–protein interactions, occurring during the various steps of the maturation process, make their structural characterization in solution particularly difficult. Paramagnetic nuclear magnetic resonance (NMR) has been used for decades to characterize chemical composition, magnetic coupling, and the electronic structure of Fe–S clusters in proteins; it represents, therefore, a powerful tool to study the protein–protein interaction networks of proteins involving into iron–sulfur cluster biogenesis. The optimization of the various NMR experiments with respect to the hyperfine interaction will be summarized here in the form of a protocol; recently developed experiments for measuring longitudinal and transverse nuclear relaxation rates in highly paramagnetic systems will be also reviewed. Finally, we will address the use of extrinsic paramagnetic centers covalently bound to diamagnetic proteins, which contributed over the last twenty years to promote the applications of paramagnetic NMR well beyond the structural biology of metalloproteins.

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