scholarly journals Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

2020 ◽  
Author(s):  
Johanne Mbianda ◽  
May Bakail ◽  
Christophe André ◽  
Gwenaëlle Moal ◽  
Marie E. Perrin ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Histone Chaperone ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Chromatin Dynamics ◽  
Correct Orientation ◽  
Surface Recognition ◽  
Binding Interface ◽  
Helical Peptide ◽  
Α Helix

<p><b>Sequence-specific oligomers with predictable folding patterns, i.e. foldamers provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may significantly contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α-helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a striking plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide. </b></p>

scholarly journals Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity

2021 ◽  
Vol 7 (12) ◽  
pp. eabd9153
Author(s):  
Johanne Mbianda ◽  
May Bakail ◽  
Christophe André ◽  
Gwenaëlle Moal ◽  
Marie E. Perrin ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Histone Chaperone ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Chromatin Dynamics ◽  
Correct Orientation ◽  
Surface Recognition ◽  
Binding Interface ◽  
Helical Peptide ◽  
Α Helix

Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may notably contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a notable plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with nonpeptide oligourea segments is the resistance to proteolysis in human plasma, which was highly improved compared to the cognate α-helical peptide.

scholarly journals Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

2020 ◽  
Author(s):  
Johanne Mbianda ◽  
May Bakail ◽  
Christophe André ◽  
Gwenaëlle Moal ◽  
Marie E. Perrin ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Histone Chaperone ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Chromatin Dynamics ◽  
Correct Orientation ◽  
Surface Recognition ◽  
Binding Interface ◽  
Helical Peptide ◽  
Α Helix

<p><b>Sequence-specific oligomers with predictable folding patterns, i.e. foldamers provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may significantly contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α-helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a striking plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide. </b></p>

scholarly journals Peptide-based inhibitors of protein–protein interactions: biophysical, structural and cellular consequences of introducing a constraint

2021 ◽  
Author(s):  
Hongshuang Wang ◽  
Robert S. Dawber ◽  
Peiyu Zhang ◽  
Martin Walko ◽  
Andrew J. Wilson ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Α Helix ◽  
Cellular Behaviour

This review summarizes the influence of inserting constraints on biophysical, conformational, structural and cellular behaviour for peptides targeting α-helix mediated protein–protein interactions.

scholarly journals Interactions between Integrase and Excisionase in the Phage Lambda Excisive Nucleoprotein Complex

2002 ◽  
Vol 184 (18) ◽  
pp. 5200-5203 ◽  
Author(s):  
Eun Hee Cho ◽  
Richard I. Gumport ◽  
Jeffrey F. Gardner
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Mobility Shift ◽  
Host Chromosome ◽  
Amino Terminal ◽  
Nucleoprotein Complex ◽  
Carboxyl Terminal ◽  
Α Helix ◽  
Gel Mobility Shift ◽  
Amino Terminal Domain

ABSTRACT Bacteriophage lambda site-specific recombination comprises two overall reactions, integration into and excision from the host chromosome. Lambda integrase (Int) carries out both reactions. During excision, excisionase (Xis) helps Int to bind DNA and introduces a bend in the DNA that facilitates formation of the proper excisive nucleoprotein complex. The carboxyl-terminal α-helix of Xis is thought to interact with Int through direct protein-protein interactions. In this study, we used gel mobility shift assays to show that the amino-terminal domain of Int maintained cooperative interactions with Xis. This finding indicates that the amino-terminal arm-type DNA binding domain of Int interacts with Xis.

scholarly journals Correction to α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53–MDM2/MDMX Protein–Protein Interactions

2020 ◽  
Vol 63 (17) ◽  
pp. 10087-10087
Author(s):  
Peng Sang ◽  
Yan Shi ◽  
Junhao Lu ◽  
Lihong Chen ◽  
Leixiang Yang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Α Helix

scholarly journals Elucidating the druggable interface of protein−protein interactions using fragment docking and coevolutionary analysis

2016 ◽  
Vol 113 (50) ◽  
pp. E8051-E8058 ◽  
Author(s):  
Fang Bai ◽  
Faruck Morcos ◽  
Ryan R. Cheng ◽  
Hualiang Jiang ◽  
José N. Onuchic
Keyword(s):  
Drug Design ◽  
Protein Interactions ◽  
Binding Sites ◽  
Hot Spots ◽  
Therapeutic Agents ◽  
Molecular Probes ◽  
Therapeutic Drug ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Fragment Docking

Protein−protein interactions play a central role in cellular function. Improving the understanding of complex formation has many practical applications, including the rational design of new therapeutic agents and the mechanisms governing signal transduction networks. The generally large, flat, and relatively featureless binding sites of protein complexes pose many challenges for drug design. Fragment docking and direct coupling analysis are used in an integrated computational method to estimate druggable protein−protein interfaces. (i) This method explores the binding of fragment-sized molecular probes on the protein surface using a molecular docking-based screen. (ii) The energetically favorable binding sites of the probes, called hot spots, are spatially clustered to map out candidate binding sites on the protein surface. (iii) A coevolution-based interface interaction score is used to discriminate between different candidate binding sites, yielding potential interfacial targets for therapeutic drug design. This approach is validated for important, well-studied disease-related proteins with known pharmaceutical targets, and also identifies targets that have yet to be studied. Moreover, therapeutic agents are proposed by chemically connecting the fragments that are strongly bound to the hot spots.

scholarly journals Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition Model

2006 ◽  
Vol 26 (8) ◽  
pp. 2887-2900 ◽  
Author(s):  
Kit I. Tong ◽  
Yasutake Katoh ◽  
Hideki Kusunoki ◽  
Ken Itoh ◽  
Toshiyuki Tanaka ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Isothermal Calorimetry ◽  
Biologically Active ◽  
Detoxification Enzymes ◽  
Bottom Surface ◽  
Transcriptional Level ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
Antioxidant Proteins ◽  
Α Helix

ABSTRACT The expression of the phase 2 detoxification enzymes and antioxidant proteins is induced at the transcriptional level by Nrf2 and negatively regulated at the posttranslational level by Keap1 through protein-protein interactions with and subsequent proteolysis of Nrf2. We found that the Neh2 domain of Nrf2 is an intrinsically disordered but biologically active regulatory domain containing a 33-residue central α-helix followed by a mini antiparallel β-sheet. Isothermal calorimetry analysis indicated that one Neh2 molecule interacts with two molecules of Keap1 via two binding sites, the stronger binding ETGE motif and the weaker binding DLG motif. Nuclear magnetic resonance titration study showed that these two motifs of the Neh2 domain bind to an overlapping site on the bottom surface of the β-propeller structure of Keap1. In contrast, the central α-helix of the Neh2 domain does not have any observable affinity to Keap1, suggesting that this region may serve as a bridge connecting the two motifs for the association with the two β-propeller structures of a dimer of Keap1. Based on these observations, we propose that Keap1 recruits Nrf2 by the ETGE motif and that the DLG motif of the Neh2 domain locks its lysine-rich central α-helix in a correct position to benefit ubiquitin signaling.

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