Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions

Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The ability of this AH to bind to other host proteins is disrupted by a neutralizing antibody derived from a human survivor of the 1995 Kikwit outbreak, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).

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Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions

F1000Research ◽

10.12688/f1000research.5573.2 ◽

2014 ◽

Vol 3 ◽

pp. 251

Author(s):

Sandeep Chakraborty ◽

Basuthkar J. Rao ◽

Bjarni Asgeirsson ◽

Abhaya M. Dandekar

Keyword(s):

West Africa ◽

Protein Interactions ◽

Rational Design ◽

Ebola Virus ◽

Structural Alignment ◽

Alpha Helix ◽

Neutralizing Antibody ◽

Protein Protein Interactions ◽

Host Proteins ◽

Alpha Helices

Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).

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Bacteria Use Structural Imperfect Mimicry To Hijack The Host Interactome

10.1101/2020.02.24.962944 ◽

2020 ◽

Cited By ~ 1

Author(s):

Natalia Sanchez de Groot ◽

Marc Torrent Burgas

Keyword(s):

Protein Interactions ◽

Rational Design ◽

Protein Protein Interactions ◽

Host Proteins ◽

Eukaryotic Proteins ◽

Host Pathogen ◽

Imperfect Mimicry ◽

The Way

ABSTRACTBacteria use protein-protein interactions to infect their hosts and hijack fundamental pathways, which ensures their survival and proliferation. Hence, the infectious capacity of the pathogen is closely related to its ability to interact with host proteins. Here, we show that hubs in the host-pathogen interactome are isolated in the pathogen network by adapting the geometry of the interacting interfaces. An imperfect mimicry of the eukaryotic interfaces allows pathogen proteins to actively bind to the host’s target while preventing deleterious effects on the pathogen interactome. Understanding how bacteria recognize eukaryotic proteins may pave the way for the rational design of new antibiotic molecules.

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Bacteria use structural imperfect mimicry to hijack the host interactome

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008395 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1008395

Author(s):

Natalia Sanchez de Groot ◽

Marc Torrent Burgas

Keyword(s):

Protein Interactions ◽

Rational Design ◽

Protein Protein Interactions ◽

Host Proteins ◽

Eukaryotic Proteins ◽

Host Pathogen ◽

Imperfect Mimicry ◽

The Way

Bacteria use protein-protein interactions to infect their hosts and hijack fundamental pathways, which ensures their survival and proliferation. Hence, the infectious capacity of the pathogen is closely related to its ability to interact with host proteins. Here, we show that hubs in the host-pathogen interactome are isolated in the pathogen network by adapting the geometry of the interacting interfaces. An imperfect mimicry of the eukaryotic interfaces allows pathogen proteins to actively bind to the host’s target while preventing deleterious effects on the pathogen interactome. Understanding how bacteria recognize eukaryotic proteins may pave the way for the rational design of new antibiotic molecules.

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Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein–Protein Interactions

The Journal of Organic Chemistry ◽

10.1021/acs.joc.0c00996 ◽

2020 ◽

Vol 85 (16) ◽

pp. 10552-10560

Author(s):

Peng Sang ◽

Yan Shi ◽

Pirada Higbee ◽

Minghui Wang ◽

Sami Abdulkadir ◽

...

Keyword(s):

Protein Interactions ◽

Rational Design ◽

Protein Protein Interactions ◽

Design And Synthesis

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Engineered pH-Sensitive Protein G / IgG Interaction

10.1101/2020.12.25.424402 ◽

2020 ◽

Author(s):

Ramesh K. Jha ◽

Allison Yankey ◽

Kalifa Shabazz ◽

Leslie Naranjo ◽

Nileena Velappan ◽

...

Keyword(s):

Binding Affinity ◽

Protein Design ◽

Protein Interactions ◽

Rational Design ◽

Protein G ◽

Acidic Ph ◽

Protein Protein Interactions ◽

Natural Interface ◽

Complex Stimuli ◽

Igg Purification

ABSTRACTWhile natural protein-protein interactions have evolved to be induced by complex stimuli, rational design of interactions that can be switched-on-demand still remain challenging in the protein design world. Here, we demonstrate a computationally redesigned natural interface for improved binding affinity could further be mutated to adopt a pH switchable interaction. The redesigned interface of Protein G-IgG Fc domain, when incorporated with histidine and glutamic acid on Protein G (PrG-EHHE), showed a switch in binding affinity by 50-fold when pH was altered from mild acidic to mild basic. The wild type (WT) interface only showed negligible switch. The overall binding affinity at mild acidic pH for PrG-EHHE outperformed the WT PrG interaction. The new reagent PrG-EHHE will be revolutionary in IgG purification since the traditional method of using an extreme acidic pH for elution can be circumvented.Abstract Figure

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Rational Design of Selective Small-Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interactions

Journal of the American Chemical Society ◽

10.1021/jacs.5b04988 ◽

2015 ◽

Vol 137 (38) ◽

pp. 12249-12260 ◽

Cited By ~ 31

Author(s):

Logan R. Hoggard ◽

Yongqiang Zhang ◽

Min Zhang ◽

Vanja Panic ◽

John A. Wisniewski ◽

...

Keyword(s):

B Cell ◽

Small Molecule ◽

Protein Interactions ◽

Rational Design ◽

Small Molecule Inhibitors ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Protein Protein Interactions ◽

Catenin B

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Protein-Protein Interactions (PPIs) as an Alternative to Targeting the ATP Binding Site of Kinase

Advances in Medical Technologies and Clinical Practice - Applied Case Studies and Solutions in Molecular Docking-Based Drug Design ◽

10.4018/978-1-5225-0362-0.ch010 ◽

2016 ◽

pp. 249-277

Author(s):

Sailu Sarvagalla ◽

Mohane Selvaraj Coumar

Keyword(s):

Protein Interactions ◽

In Silico ◽

Rational Design ◽

Kinase Activity ◽

Hot Spot ◽

Binding Pocket ◽

Atp Binding ◽

Protein Protein Interactions ◽

Structure Based Drug Design ◽

Atp Binding Site

Most of the developed kinase inhibitor drugs are ATP competitive and suffer from drawbacks such as off-target kinase activity, development of resistance due to mutation in the ATP binding pocket and unfavorable intellectual property situations. Besides the ATP binding pocket, protein kinases have binding sites that are involved in Protein-Protein Interactions (PPIs); these PPIs directly or indirectly regulate the protein kinase activity. Of recent, small molecule inhibitors of PPIs are emerging as an alternative to ATP competitive agents. Rational design of inhibitors for kinase PPIs could be carried out using molecular modeling techniques. In silico tools available for the prediction of hot spot residues and cavities at the PPI sites and the means to utilize this information for the identification of inhibitors are discussed. Moreover, in silico studies to target the Aurora B-INCENP PPI sites are discussed in context. Overall, this chapter provides detailed in silico strategies that are available to the researchers for carrying out structure-based drug design of PPI inhibitors.

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Protein–Protein Interactions Affect Alpha Helix Stability in Crowded Environments

The Journal of Physical Chemistry B ◽

10.1021/jp512630s ◽

2015 ◽

Vol 119 (7) ◽

pp. 2956-2967 ◽

Cited By ~ 16

Author(s):

Bryanne Macdonald ◽

Shannon McCarley ◽

Sundus Noeen ◽

Alan E. van Giessen

Keyword(s):

Protein Interactions ◽

Alpha Helix ◽

Protein Protein Interactions ◽

Helix Stability ◽

Crowded Environments

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Detection of the Potyviral Genome-Linked Protein VPg in Virions and Its Phosphorylation by Host Kinases

Journal of Virology ◽

10.1128/jvi.76.24.12703-12711.2002 ◽

2002 ◽

Vol 76 (24) ◽

pp. 12703-12711 ◽

Cited By ~ 48

Author(s):

Pietri Puustinen ◽

Minna-Liisa Rajamäki ◽

Konstantin I. Ivanov ◽

Jari P. T. Valkonen ◽

Kristiina Mäkinen

Keyword(s):

Protein Interactions ◽

Kinase Activity ◽

Systemic Infection ◽

Proximal Part ◽

Infection Cycle ◽

Protein Protein Interactions ◽

Host Proteins ◽

Solanum Commersonii ◽

Wild Potato Species ◽

Potato Virus A

ABSTRACT The multifunctional genome-linked protein (VPg) of Potato virus A (PVA; genus Potyvirus) was found to be phosphorylated as a part of the virus particle by a cellular kinase activity from tobacco. Immunoprecipitation, immunolabeling, and immunoelectron microscopy experiments showed that VPg is exposed at one end of the virion and it is accessible to protein-protein interactions. Substitution Ser185Leu at the C-proximal part of VPg reduces accumulation of PVA in inoculated leaves of the wild potato species Solanum commersonii and delays systemic infection, which is not observed in tobacco plants. Our data show that kinases of S. commersonii differentially recognize the VPg containing Ser or Leu at position 185, whereas both forms of VPg are similarly recognized by tobacco kinases. Taken together, our data imply that the virion-bound VPg may interact with host proteins and that phosphorylation of VPg may play a role in the VPg-mediated functions during the infection cycle of potyviruses.

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