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Proteins May 2016Phosphorylation is an important post-translational modification that regulates protein function by the attachment of negatively charged phosphate groups to...
Phosphorylation is an important post-translational modification that regulates protein function by the attachment of negatively charged phosphate groups to phosphorylatable amino acid residues. As a mode of action, an influence of phosphorylation on the binding of compounds to proteins has been discussed and described for a number of proteins in the literature. However, a systematic statistical survey probing for enriched phosphorylation sites close to compound binding sites in support of this notion and with properly chosen random reference distributions has not been presented yet. Using high-resolution protein structures from the Protein Data Bank including their co-crystallized non-covalently bound compounds and experimentally determined phosphorylation sites, we analyzed the pairwise distance distributions of phosphorylation and compound binding sites on protein surfaces. We found that phosphorylation sites are indeed located at significantly closer distances to compounds than expected by chance holding true specifically also for the subset of compound binding sites serving as catalytic sites of metabolic reactions. This tendency was particularly evident when treating phosphorylation sites as collective sets supporting the relevance of phosphorylation hotspots. Interestingly, phosphorylation sites were found to be closer to negatively charged than to positively charged compounds suggesting a stronger modulation of the binding of negatively charged compounds in dependence on phosphorylation status than on positively charged compounds. The enrichment of phosphorylation sites near compound binding sites confirms a regulatory role of phosphorylation in compound binding and provides a solid statistical basis for the literature-reported selected events.
Topics: Humans; Phosphorylation; Protein Binding; Protein Conformation; Proteins; Static Electricity
PubMed: 26817627
DOI: 10.1002/prot.25001 -
Handbook of Experimental Pharmacology 2008Cell physiology is governed by an intricate mesh of physical and functional links among proteins, nucleic acids and other metabolites. The recent information flood... (Review)
Review
Cell physiology is governed by an intricate mesh of physical and functional links among proteins, nucleic acids and other metabolites. The recent information flood coming from large-scale genomic and proteomic approaches allows us to foresee the possibility of compiling an exhaustive list of the molecules present within a cell, enriched with quantitative information on concentration and cellular localization. Moreover, several high-throughput experimental and computational techniques have been devised to map all the protein interactions occurring in a living cell. So far, such maps have been drawn as graphs where nodes represent proteins and edges represent interactions. However, this representation does not take into account the intrinsically modular nature of proteins and thus fails in providing an effective description of the determinants of binding. Since proteins are composed of domains that often confer on proteins their binding capabilities, a more informative description of the interaction network would detail, for each pair of interacting proteins in the network, which domains mediate the binding. Understanding how protein domains combine to mediate protein interactions would allow one to add important features to the protein interaction network, making it possible to discriminate between simultaneously occurring and mutually exclusive interactions. This objective can be achieved by experimentally characterizing domain recognition specificity or by analyzing the frequency of co-occurring domains in proteins that do interact. Such approaches allow gaining insights on the topology of complexes with unknown three-dimensional structure, thus opening the prospect of adopting a more rational strategy in developing drugs designed to selectively target specific protein interactions.
Topics: Drug Delivery Systems; Humans; Protein Binding; Protein Interaction Mapping; Protein Structure, Tertiary; Signal Transduction
PubMed: 18491061
DOI: 10.1007/978-3-540-72843-6_16 -
Methods in Enzymology 2006Glycolipids are found on all eukaryotic cells. Their expression varies among tissues, with the highest density found in the brain, where glycolipids are the most... (Review)
Review
Glycolipids are found on all eukaryotic cells. Their expression varies among tissues, with the highest density found in the brain, where glycolipids are the most abundant of all glycoconjugate classes. In addition to playing roles in membrane structure, glycolipids also act as cell surface recognition molecules, mediating cell-cell interactions, as well as binding certain pathogens and toxins. Because of their amphipathic nature, underivatized glycolipids are amenable to immobilization on hydrophobic surfaces, where they can be probed with lectins, antibodies, pathogens, toxins, and intact cells to reveal their binding specificities and affinities. Three particularly useful methods to probe specific glycolipid-mediated recognition events are microwell adsorption (ELISA), thin layer chromatography overlay, and surface plasmon resonance (SPR) spectroscopy.
Topics: Animals; Glycolipids; Humans; Protein Binding; Proteins
PubMed: 17132507
DOI: 10.1016/S0076-6879(06)17015-9 -
Bioanalysis Nov 2020
Topics: Child; Drug Development; Humans; Protein Binding
PubMed: 33078957
DOI: 10.4155/bio-2020-0237 -
Biological Chemistry Nov 2013Disrupted-in-Schizophrenia 1 (DISC1) is a widely-accepted genetic risk factor for schizophrenia and many other major mental illnesses. Traditionally DISC1 has been... (Review)
Review
Disrupted-in-Schizophrenia 1 (DISC1) is a widely-accepted genetic risk factor for schizophrenia and many other major mental illnesses. Traditionally DISC1 has been referred to as a 'scaffold protein' because of its ability to bind to a wide array of other proteins, including those of importance for neurodevelopment. Here, we review the characteristic properties shared between established scaffold proteins and DISC1. We find DISC1 to have many, but not all, of the characteristics of a scaffold protein, as it affects a considerable number of different, but related, signaling pathways, in most cases through inhibition of key enzymes. Using threading algorithms, the C-terminal portion of DISC1 could be mapped to extended helical structures, yet it may not closely resemble any of the known tertiary folds. While not completely fitting the classification of a classical scaffold protein, DISC1 does appear to be a tightly regulated and multi-faceted inhibitor of a wide range of enzymes from interrelated signaling cascades (Diverse Inhibitor of Signaling Cascades), which together contribute to neurodevelopment and synaptic homeostasis. Consequently, disruption of this complex regulation would be expected to lead to the range of major mental illnesses in which the DISC1 gene has been implicated.
Topics: Humans; Mental Disorders; Models, Molecular; Nerve Tissue Proteins; Nuclear Matrix-Associated Proteins; Protein Binding; Protein Transport; Signal Transduction
PubMed: 23832957
DOI: 10.1515/hsz-2013-0178 -
Annual Review of Pharmacology and... Jan 2017Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has... (Review)
Review
Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has been increased interest in targeting them using peptide-based therapeutics. Peptides benefit from being specific, relatively safe, and easy to produce. They are also easy to modify using chemical synthesis and molecular biology techniques. However, significant challenges remain regarding the use of peptides as therapeutic agents. Identification of peptide motifs is difficult, and peptides typically display low cell permeability and sensitivity to enzymatic degradation. In this review, we outline the principal high-throughput methodologies for motif discovery and describe current methods for overcoming pharmacokinetic and bioavailability limitations.
Topics: Animals; Drug Discovery; Humans; Peptide Library; Peptides; Protein Binding; Protein Interaction Domains and Motifs
PubMed: 27618737
DOI: 10.1146/annurev-pharmtox-010716-104805 -
Nature Reviews. Endocrinology Jun 2011Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with endocrine diseases.... (Review)
Review
Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with endocrine diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several diseases with classic hypophenotypes or hyperphenotypes of the target endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology.
Topics: Endocrine System Diseases; Humans; Models, Biological; Mutation; Protein Binding; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 21301490
DOI: 10.1038/nrendo.2011.20 -
Current Drug Targets May 2004Poly(ADP-ribose) polymerization is a unique post-translation protein modification that utilizes an ADP-ribose moiety from NAD+ to form long and branched polymers... (Review)
Review
Poly(ADP-ribose) polymerization is a unique post-translation protein modification that utilizes an ADP-ribose moiety from NAD+ to form long and branched polymers attached via glutamic acid residues to nuclear acceptor proteins. The corresponding enzyme, poly(ADP-ribose) polymerase (PARP-1), is a zinc finger-containing protein, which allows PARP-1 binding to either double- or single-strand DNA breaks. The catalytic activity of PARP-1 is strictly dependent on the presence of strand breaks in DNA, and is modulated by the level of automodification. PARP-1 is regarded as an intracellular sensor for DNA strand breaks, and its function has been implicated in cellular processes that require DNA cleavage and rejoining reactions, such as DNA replication, recombination and repair. Recent studies have also implicated PARP-1 in the regulation of gene expression through modification of transcription factors by poly(ADP-ribosyl)ation or its direct binding to gene-regulating DNA sequences. The latter is attributable to PARP's ability to recognize and bind to various structural discontinuities in the DNA duplex in the absence of DNA strand breaks, such as three- or four-way junctions, bent DNA, and base unpaired regions. Cumulatively, these findings indicate that PARP-1 plays a pivotal role in the maintenance of the genome integrity during the normal functioning of eukaryotic cells as well as in the cellular responses to DNA damage, and that PARP-DNA interactions are indispensable for PARP function. This review summarizes the data on DNA-binding properties of PARP-1 and relates them to the development of strategies for sensitizing tumor cells to genotoxic treatments.
Topics: Animals; Antineoplastic Agents; DNA; Drug Delivery Systems; Humans; Neoplasms; Poly Adenosine Diphosphate Ribose; Protein Binding
PubMed: 15134218
DOI: 10.2174/1389450043345498 -
Rational Drug Therapy Sep 1984
Review
Topics: Aging; Blood Proteins; Disease; Drug Interactions; Drug Therapy; Humans; Pharmaceutical Preparations; Protein Binding; Saliva; Ultrafiltration
PubMed: 6399119
DOI: No ID Found -
Journal of Molecular Recognition : JMR 2002Protein-protein interactions form the proteinaceous network, which plays a central role in numerous processes in the cell. This review highlights the main structures,... (Review)
Review
Protein-protein interactions form the proteinaceous network, which plays a central role in numerous processes in the cell. This review highlights the main structures, properties of contact surfaces, and forces involved in protein-protein interactions. The properties of protein contact surfaces depend on their functions. The characteristics of contact surfaces of short-lived protein complexes share some similarities with the active sites of enzymes. The contact surfaces of permanent complexes resemble domain contacts or the protein core. It is reasonable to consider protein-protein complex formation as a continuation of protein folding. The contact surfaces of the protein complexes have unique structure and properties, so they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations have been undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or on the other hand, induce protein dimerization.
Topics: Animals; Binding Sites; Humans; Protein Binding; Protein Interaction Mapping; Proteins
PubMed: 12501160
DOI: 10.1002/jmr.597