scholarly journals Targeting Difficult Protein-Protein Interactions with Plain and General Computational Approaches

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2256 ◽  
Author(s):  
Mariarosaria Ferraro ◽  
Giorgio Colombo
Keyword(s):  
Protein Interactions ◽  
Signaling Networks ◽  
Protein Protein Interactions ◽  
Structural Dynamic ◽  
Antibody Recognition ◽  
Disease States ◽  
Interfacial Areas ◽  
Interacting Surfaces ◽  
Cell Signaling Networks ◽  
Antigen Antibody

Investigating protein-protein interactions (PPIs) holds great potential for therapeutic applications, since they mediate intricate cell signaling networks in physiological and disease states. However, their complex and multifaceted nature poses a major challenge for biochemistry and medicinal chemistry, thereby limiting the druggability of biological partners participating in PPIs. Molecular Dynamics (MD) provides a solid framework to study the reciprocal shaping of proteins’ interacting surfaces. Here, we review successful applications of MD-based methods developed in our group to predict interfacial areas involved in PPIs of pharmaceutical interest. We report two interesting examples of how structural, dynamic and energetic information can be combined into efficient strategies which, complemented by experiments, can lead to the design of new small molecules with promising activities against cancer and infections. Our advances in targeting key PPIs in angiogenic pathways and antigen-antibody recognition events will be discussed for their role in drug discovery and chemical biology.

scholarly journals Targeting protein–protein interactions by rational design: mimicry of protein surfaces

2006 ◽  
Vol 3 (7) ◽  
pp. 215-233 ◽  
Author(s):  
Steven Fletcher ◽  
Andrew D Hamilton
Keyword(s):  
Protein Interactions ◽  
Active Site ◽  
Rational Design ◽  
Considerable Progress ◽  
Biological Processes ◽  
Protein Protein Interactions ◽  
Protein Surfaces ◽  
Enzyme Active Site ◽  
Novel Therapeutics ◽  
Interfacial Areas

Protein–protein interactions play key roles in a range of biological processes, and are therefore important targets for the design of novel therapeutics. Unlike in the design of enzyme active site inhibitors, the disruption of protein–protein interactions is far more challenging, due to such factors as the large interfacial areas involved and the relatively flat and featureless topologies of these surfaces. Nevertheless, in spite of such challenges, there has been considerable progress in recent years. In this review, we discuss this progress in the context of mimicry of protein surfaces: targeting protein–protein interactions by rational design.

scholarly journals Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins

2018 ◽  
Vol 4 (10) ◽  
pp. eaau4130 ◽  
Author(s):  
Per Jemth ◽  
Elin Karlsson ◽  
Beat Vögeli ◽  
Brenda Guzovsky ◽  
Eva Andersson ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Solvent Accessible Surface Area ◽  
Resonance Spectroscopy ◽  
Protein Protein Interactions ◽  
Structural Dynamic ◽  
Intrinsically Disordered ◽  
Structure And Dynamics

In every established species, protein-protein interactions have evolved such that they are fit for purpose. However, the molecular details of the evolution of new protein-protein interactions are poorly understood. We have used nuclear magnetic resonance spectroscopy to investigate the changes in structure and dynamics during the evolution of a protein-protein interaction involving the intrinsically disordered CREBBP (CREB-binding protein) interaction domain (CID) and nuclear coactivator binding domain (NCBD) from the transcriptional coregulators NCOA (nuclear receptor coactivator) and CREBBP/p300, respectively. The most ancient low-affinity “Cambrian-like” [540 to 600 million years (Ma) ago] CID/NCBD complex contained less secondary structure and was more dynamic than the complexes from an evolutionarily younger “Ordovician-Silurian” fish ancestor (ca. 440 Ma ago) and extant human. The most ancient Cambrian-like CID/NCBD complex lacked one helix and several interdomain interactions, resulting in a larger solvent-accessible surface area. Furthermore, the most ancient complex had a high degree of millisecond-to-microsecond dynamics distributed along the entire sequences of both CID and NCBD. These motions were reduced in the Ordovician-Silurian CID/NCBD complex and further redistributed in the extant human CID/NCBD complex. Isothermal calorimetry experiments show that complex formation is enthalpically favorable and that affinity is modulated by a largely unfavorable entropic contribution to binding. Our data demonstrate how changes in structure and motion conspire to shape affinity during the evolution of a protein-protein complex and provide direct evidence for the role of structural, dynamic, and frustrational plasticity in the evolution of interactions between intrinsically disordered proteins.

The Hydrocarbon Staple & Beyond: Recent Advances Towards Stapled Peptide Therapeutics that Target Protein-Protein Interactions

2018 ◽  
Vol 18 (7) ◽  
pp. 611-624 ◽  
Author(s):  
Robert A. Hillman ◽  
Jonathan W. Nadraws ◽  
Michael A. Bertucci
Keyword(s):  
Protein Interactions ◽  
Neurological Disorders ◽  
Endocrine Disorders ◽  
Protein Protein Interactions ◽  
Peptide Therapeutics ◽  
Stapled Peptide ◽  
Disease States ◽  
Structural Rigidity ◽  
Recent Advances ◽  
Pharmacokinetic Properties

Anomalous protein-protein interactions (PPIs) have been correlated to a variety of disease states, such as cancer, infectious disease, neurological disorders, diabetes, endocrine disorders and cardiovascular disease. Stapled peptides are an emerging intervention for these PPIs due to their improved structural rigidity and pharmacokinetic properties relative to unstapled peptides. This review details the most recent advances in the field of stapled peptide therapeutics, including the increasing variety of PPIs being targeted and types of peptide staples being employed.

scholarly journals Integrative proteomics reveals exceptional diversity and versatility of mammalian humoral immunity

2020 ◽  
Author(s):  
Yufei Xiang ◽  
Zhe Sang ◽  
Lirane Bitton ◽  
Jianquan Xu ◽  
Yang Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Interactions ◽  
Specific Antigen ◽  
Cellular Protein ◽  
Protein Protein Interactions ◽  
Humoral Immune ◽  
High Affinity ◽  
Interaction Interface ◽  
Systematic Understanding ◽  
Antigen Antibody

SummaryThe humoral immune response is essential for the survival of mammals. However, we still lack a systematic understanding of the specific serologic antibody repertoire in response to an antigen. We developed a proteomic strategy to survey, at an unprecedented scale, the landscapes of antigen-engaged, serum-circulating repertoires of camelid heavy-chain antibodies (hcAbs). The sensitivity and robustness of this technology were validated using three antigens spanning orders of magnitude in immune response; thousands of divergent, high-affinity hcAb families were confidently identified and quantified. Using high-throughput structural modeling, cross-linking mass spectrometry, mutagenesis, and deep learning, we mapped and analyzed the epitopes of > 100,000 antigen-antibody complexes. Our results revealed a surprising diversity of high-affinity hcAbs for specific antigen binding on a variety of dominant epitopes. hcAbs perfect both shape and charge complementarity to target challenging antigens specifically; they can rapidly evolve to recognize a conserved, promiscuous cellular protein interaction interface, unraveling the convergent force that drives protein-protein interactions.

scholarly journals Application of TurboID-mediated proximity labeling for mapping a GSK3 kinase signaling network in Arabidopsis

2019 ◽  
Author(s):  
Tae-Wuk Kim ◽  
Chan Ho Park ◽  
Chuan-Chih Hsu ◽  
Jia-Ying Zhu ◽  
Yuchun Hsiao ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Transgenic Arabidopsis ◽  
Affinity Purification ◽  
High Specificity ◽  
Signaling Network ◽  
Signaling Networks ◽  
Protein Protein Interactions ◽  
Quantitative Mass Spectrometry ◽  
Cellular Regulation ◽  
Biotin Ligase

AbstractTransient protein-protein interactions (PPIs), such as those between posttranslational modifying enzymes and their substrates, play key roles in cellular regulation, but are difficult to identify. Here we demonstrate the application of enzyme-catalyzed proximity labeling (PL), using the engineered promiscuous biotin ligase TurboID, as a sensitive method for characterizing PPIs in signaling networks. We show that TurboID fused with the GSK3-like kinase BIN2 or a PP2A phosphatase biotinylates their known substrate, the BZR1 transcription factor, with high specificity and efficiency. We optimized the protocol of biotin labeling and affinity purification in transgenic Arabidopsis expressing a BIN2-TurboID fusion protein. Subsequent quantitative mass spectrometry (MS) analysis identified about three hundred proteins biotinylated by BIN2-TurboID more efficiently than the YFP-TurboID control. These include a significant subset of previously proven BIN2 interactors and a large number of new BIN2-proximal proteins that uncover a broad BIN2 signaling network. Our study illustrates that PL-MS using TurboID is a powerful tool for mapping signaling networks, and reveals broad roles of BIN2 kinase in cellular signaling and regulation in plants.Impact StatementTurboID-mediated proximity labeling is a powerful tool for protein interactomics in plants.

scholarly journals Modeling role of pyruvate in the processes of protein-protein interaction

2015 ◽  
Vol 61 (1) ◽  
pp. 132-140
Author(s):  
F.N. Gylmiyarova ◽  
V.M. Radomskaya ◽  
O.A. Gusyakova ◽  
E.A. Ryskina ◽  
N.A. Kolotyeva ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Laser Scanning ◽  
Laser Scanning Confocal Microscopy ◽  
Molecular Probes ◽  
Antigenic Determinants ◽  
Protein Protein Interactions ◽  
Regulatory Pathways ◽  
Protein Protein Interaction ◽  
Scanning Confocal Microscopy ◽  
Antigen Antibody

Using the ABO antibody-antigen model the influence of natural metabolite pyruvate on the antibody interaction with of erythrocyte antigens, defining their group specificity has been investigated. Before agglutination reaction erythrocytes of A(II)-AB(IV) blood groups, monoclonal anti-A and anti-B antibodies were incubated with sodium pyruvate. Visualization of agglutinates was performed by means of flow cytometry and laser scanning confocal microscopy. Computer-aided prediction of the spectrum of biological activity of pyruvate by a PASS program proposed major regulatory pathways, in which pyruvate may be involved. It has been demonstrated that pyruvate can regulate the intensity of antigen-antibody interaction. These results suggest the possibility of using small molecules, for example pyruvate, as molecular probes and prospects of the use of erythrocytes with antigenic determinants of the ABO system expressed on their membranes for studies of protein-protein interactions due to convenient visualization and possibility of quantitative evaluation of this process.

scholarly journals Analysis of signaling networks distributed over intracellular compartments based on protein-protein interactions

BMC Genomics ◽  
2014 ◽  
Vol 15 (Suppl 12) ◽  
pp. S7 ◽  
Author(s):  
Olga Popik ◽  
Olga Saik ◽  
Evgeny Petrovskiy ◽  
Björn Sommer ◽  
Ralf Hofestädt ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Signaling Networks ◽  
Protein Protein Interactions ◽  
Intracellular Compartments
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