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Trends in Plant Science Jun 2017The application of RNA interactome capture to plants has enabled comprehensive determination of the plant RNA-binding proteome and the identification of novel families... (Review)
Review
The application of RNA interactome capture to plants has enabled comprehensive determination of the plant RNA-binding proteome and the identification of novel families of RNA-binding proteins (RBPs). The technique is providing insight into the evolution of the eukaryotic repertoire of RBPs and will enhance prospects for engineering RBPs to improve crop traits.
Topics: Plant Proteins; Protein Binding; RNA, Plant; RNA-Binding Proteins
PubMed: 28478905
DOI: 10.1016/j.tplants.2017.04.006 -
Cell Reports Mar 2018It has been suggested that the evolution of protein complexes is significantly influenced by stochastic, non-adaptive processes. Using ligand binding as a proxy of...
It has been suggested that the evolution of protein complexes is significantly influenced by stochastic, non-adaptive processes. Using ligand binding as a proxy of function, we show that the structure of ligand-binding sites significantly influences the evolution of protein complexes. We show that homomers with multi-chain binding sites (MBSs) evolve new functions slower than monomers or other homomers, and those binding cofactors and metals have more conserved quaternary structure than other homomers. Moreover, the ligands and ligand-binding pockets of homologous MBS homomers are more similar than monomers and other homomers. Our results suggest strong evolutionary selection for quaternary structure in cofactor-binding MBS homomers, whereas neutral processes are more important in complexes with single-chain binding sites. They also have pharmacological implications, suggesting that complexes with single-chain binding sites are better targets for selective drugs, whereas MBS homomers are good candidates for broad-spectrum antibiotic and multitarget drug design.
Topics: Binding Sites; Humans; Ligands; Protein Binding
PubMed: 29562182
DOI: 10.1016/j.celrep.2018.02.085 -
Current Opinion in Structural Biology Aug 2016Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of... (Review)
Review
Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of studies report novel helical peptide inhibitors of protein-protein interactions. New techniques have been developed for peptide design and for chemically stabilizing peptides in a helical conformation, which frequently improves protease resistance and cell permeability. We summarize advances in peptide crosslinking chemistry and give examples of peptide design studies targeting coiled-coil transcription factors, Bcl-2 family proteins, MDM2/MDMX, and HIV gp41, among other targets.
Topics: Animals; Drug Design; Humans; Peptides; Protein Binding; Protein Conformation, alpha-Helical; Proteins
PubMed: 27123812
DOI: 10.1016/j.sbi.2016.04.001 -
Glycoconjugate Journal Oct 2015This review discusses the challenges facing research in 'functional glycomics' and the novel technologies that are being developed to advance the field. The structural... (Review)
Review
This review discusses the challenges facing research in 'functional glycomics' and the novel technologies that are being developed to advance the field. The structural complexity of glycans and glycoconjugates makes studies of both their structures and recognition difficult. However, these intricate structures can be captured from their natural sources, isolated and fluorescently-tagged for detailed structural analysis and for presentation on glycan microarrays for functional recognition by glycan-binding proteins. These advances in glycan preparation and manipulation enable the streamlining of functional glycomics studies and will help to propel the field forward in studying natural, biologically relevant glycans.
Topics: Glycoconjugates; Glycomics; Humans; Microarray Analysis; Polysaccharides; Protein Binding; Proteins
PubMed: 25877830
DOI: 10.1007/s10719-015-9584-8 -
Nature Chemical Biology Apr 2020Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus... (Review)
Review
Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these 'bifunctional' small molecules facilitate the study of an increasingly wide range of complex biological phenomena and enable the drugging of otherwise challenging therapeutic targets and processes. Despite their structural and functional differences, all bifunctional molecules employ Nature's strategy of altering interactomes and inducing proximity to modulate biology. They therefore exhibit a shared set of chemical and biophysical principles that have not yet been appreciated fully. By highlighting these commonalities-and their wide-ranging consequences-we hope to chip away at the artificial barriers that threaten to constrain this interdisciplinary field. Doing so promises to yield remarkable benefits for biological research and therapeutics discovery.
Topics: Animals; Humans; Protein Binding; Protein Interaction Domains and Motifs; Proteins; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 32198490
DOI: 10.1038/s41589-020-0469-1 -
Biochemical Pharmacology Mar 2021Aryl hydrocarbon receptor (AHR) was initially discovered as a cellular protein involved in mediating the detoxification of xenobiotic compounds. Extensive research in... (Review)
Review
Aryl hydrocarbon receptor (AHR) was initially discovered as a cellular protein involved in mediating the detoxification of xenobiotic compounds. Extensive research in the past two decades has identified several families of physiological ligands and uncovered important functions of AHR in normal development and homeostasis. Deficiency in AHR expression disrupts major signaling systems and transcriptional programs, which appear to be responsible for the development of numerous developmental abnormalities including cardiac hypertrophy and epidermal hyperplasia. This mini review primarily summarizes recent advances in our understanding of AHR functions in normal physiology with an emphasis on the cardiovascular, gastrointestinal, integumentary, nervous, and immunomodulatory systems.
Topics: Animals; Gastrointestinal Tract; Humans; Immune System; Ligands; Nervous System Physiological Phenomena; Protein Binding; Receptors, Aryl Hydrocarbon; Signal Transduction; Xenobiotics
PubMed: 33515530
DOI: 10.1016/j.bcp.2021.114428 -
Clinical and Translational Science Nov 2023Extracellular chemical concentrations are considered physiologically relevant for in vitro testing and are evaluated in traditional in vitro systems using cell culture...
Extracellular chemical concentrations are considered physiologically relevant for in vitro testing and are evaluated in traditional in vitro systems using cell culture media containing 5%-10% fetal bovine serum (FBS). However, depending on the physicochemical properties, and in vitro testing conditions, cells could be exposed to variable unbound extracellular concentrations. If in vitro unbound concentrations are not calculated, it is challenging to distinguish the chemical potency and concentration-driven responses. In this study, one- and two-protein binding models were used to estimate protein binding corrected chemical concentrations of various chemicals for in vitro testing. As ceftizoxime, moxifloxacin, and nicotine have low protein binding affinity, the in vitro protein binding in 5%-10% FBS is less than 5% and can be considered negligible. However, protein binding of moderate and highly protein-bound chemicals must be corrected for as the in vitro unbound concentrations in 5%-10% FBS containing cell culture media will vary over a range of chemical concentrations. In vitro pharmacological and toxicological assessments must incorporate protein binding-adjusted in vitro concentrations to ensure physiologically relevant exposures. A user-friendly Excel spreadsheet is provided to help bench scientists calculate protein binding-corrected chemical concentrations for in vitro testing.
Topics: Humans; Protein Binding; In Vitro Techniques
PubMed: 37605430
DOI: 10.1111/cts.13616 -
Proceedings of the National Academy of... Dec 2019Protein multivalency can provide increased affinity and specificity relative to monovalent counterparts, but these emergent biochemical properties and their mechanistic...
Protein multivalency can provide increased affinity and specificity relative to monovalent counterparts, but these emergent biochemical properties and their mechanistic underpinnings are difficult to predict as a function of the biophysical properties of the multivalent binding partners. Here, we present a mathematical model that accurately simulates binding kinetics and equilibria of multivalent protein-protein interactions as a function of the kinetics of monomer-monomer binding, the structure and topology of the multidomain interacting partners, and the valency of each partner. These properties are all experimentally or computationally estimated a priori, including approximating topology with a worm-like chain model applicable to a variety of structurally disparate systems, thus making the model predictive without parameter fitting. We conceptualize multivalent binding as a protein-protein interaction network: ligand and receptor valencies determine the number of interacting species in the network, with monomer kinetics and structural properties dictating the dynamics of each species. As predicted by the model and validated by surface plasmon resonance experiments, multivalent interactions can generate several noncanonical macroscopic binding dynamics, including a transient burst of high-energy configurations during association, biphasic equilibria resulting from interligand competition at high concentrations, and multiexponential dissociation arising from differential lifetimes of distinct network species. The transient burst was only uncovered when extending our analysis to trivalent interactions due to the significantly larger network, and we were able to predictably tune burst magnitude by altering linker rigidity. This study elucidates mechanisms of multivalent binding and establishes a framework for model-guided analysis and engineering of such interactions.
Topics: Computational Biology; Computer Simulation; Kinetics; Models, Molecular; Protein Binding; Protein Interaction Maps; Surface Plasmon Resonance
PubMed: 31776263
DOI: 10.1073/pnas.1902909116 -
Acta Pharmacologica Sinica Aug 2013Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits... (Review)
Review
Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.
Topics: Allosteric Regulation; Animals; Blood Proteins; Humans; Pharmaceutical Preparations; Protein Binding; Stereoisomerism
PubMed: 23852086
DOI: 10.1038/aps.2013.78 -
Journal of Chromatography. B,... Oct 2014Cellular membrane affinity chromatography stationary phases have been extensively used to characterize immobilized proteins and provide a direct measurement of multiple... (Review)
Review
Cellular membrane affinity chromatography stationary phases have been extensively used to characterize immobilized proteins and provide a direct measurement of multiple binding sites, including orthosteric and allosteric sites. This review will address the utilization of immobilized cellular and tissue fragments to characterize multiple transmembrane proteins co-immobilized onto a stationary phase. This approach will be illustrated by demonstrating that multiple transmembrane proteins were immobilized from cell lines and tissue fragments. In addition, the immobilization of individual compartments/organelles within a cell will be discussed and the changes in the proteins binding/kinetics based on their location.
Topics: Binding Sites; Chromatography, Affinity; Humans; Immobilized Proteins; Kinetics; Ligands; Membrane Proteins; Protein Binding
PubMed: 24780640
DOI: 10.1016/j.jchromb.2014.04.005