Structure-based peptide design targeting intrinsically disordered proteins: Novel histone H4 and H2A peptidic inhibitors

Wichapong, Kanin; Silvestre-Roig, Carlos; Braster, Quinte; Schumski, Ariane; Soehnlein, Oliver; Nicolaes, Gerry A. F.

doi:10.1016/j.csbj.2021.01.026

Cited by 22 publications

(20 citation statements)

References 59 publications

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“…Thus, pharmacological approaches to target the C-terminal IDPR to stabilize CLEC16A could prove protective against disease. Indeed, there has been growing interest and development in therapeutics targeting IDPRs (65). Interestingly, IDPRs can also retain functionality when expressed independently as truncated fragments (66)(67)(68).…”

Section: Discussionmentioning

confidence: 99%

The human disease geneCLEC16Aencodes an intrinsically disordered protein region required for mitochondrial quality control

Gingerich

Liu

Chai

et al. 2021

Preprint

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CLEC16A regulates mitochondrial health through mitophagy and is associated with over 20 human diseases. While CLEC16A has ubiquitin ligase activity, the key structural and functional regions of CLEC16A, and their relevance for human disease, remain unknown. Here, we report that a disease-associated CLEC16A variant lacks a C-terminal intrinsically disordered protein region (IDPR) that is critical for mitochondrial quality control. Using carbon detect NMR, we find that the CLEC16A C terminus lacks secondary structure, validating the presence of an IDPR. Loss of the CLEC16A C-terminal IDPR in vivo impairs pancreatic β-cell mitophagy, mitochondrial function, and glucose-stimulated insulin secretion, ultimately causing glucose intolerance. Deletion of the CLEC16A C-terminal IDPR increases its self-ubiquitination and destabilizes CLEC16A, thus impairing formation of a critical CLEC16A-dependent mitophagy complex. Importantly, CLEC16A stability is dependent on proline bias within the C-terminal IDPR, but not amino acid sequence order or charge. Together, we clarify how an IDPR in CLEC16A prevents diabetes, thus implicating the disruption of IDPRs as novel pathological contributors to diabetes and other CLEC16A-associated diseases.

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Section: Discussionmentioning

confidence: 99%

The human disease geneCLEC16Aencodes an intrinsically disordered protein region required for mitochondrial quality control

Gingerich

Liu

Chai

et al. 2021

Preprint

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“…To predict the binding efficacy, we subjected published structures of the bimolecular GPIbα-VWF A1 complex and the trimolecular GPIbα-VWF A1-botrocetin complex, and we used molecular dynamic simulations to reveal key interacting regions at the complexed inter-molecular interfaces. The simulations were based on established and published protocols using standard parameter settings [37].…”

Section: Design and Synthesis Of Cyclic Gpibα-mimicking Peptides Bind...mentioning

confidence: 99%

“…The GPIbα-VWF A1 domain complex and the GPIbα-VWF A1-botrocetin complex (PDB code: 1U0N) were subjected to molecular dynamics (MD) simulations in order to identify key interacting residues at the interface according to a previously established method [37,52]. Herein, AMBER14SB force fields were assigned for proteins and a TIP3P water model was used and added to a 10 Å radius of the molecular surface of the complex.…”

Section: Molecular Dynamics and Binding Free-energy Calculationsmentioning

confidence: 99%

Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

Hrdinová

Fernández

Ercig

et al. 2022

IJMS

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The plasmatic von Willebrand factor (VWF) circulates in a compact form unable to bind platelets. Upon shear stress, the VWF A1 domain is exposed, allowing VWF-binding to platelet glycoprotein Ib-V-IX (GPIbα chain). For a better understanding of the role of this interaction in cardiovascular disease, molecules are needed to specifically interfere with the opened VWF A1 domain interaction with GPIbα. Therefore, we in silico designed and chemically synthetized stable cyclic peptides interfering with the platelet-binding of the VWF A1 domain per se or complexed with botrocetin. Selected peptides (26–34 amino acids) with the lowest-binding free energy were: the monocyclic mono- vOn Willebrand factoR-GPIbα InTerference (ORbIT) peptide and bicyclic bi-ORbIT peptide. Interference of the peptides in the binding of VWF to GPIb-V-IX interaction was retained by flow cytometry in comparison with the blocking of anti-VWF A1 domain antibody CLB-RAg35. In collagen and VWF-dependent whole-blood thrombus formation at a high shear rate, CLB-RAg35 suppressed stable platelet adhesion as well as the formation of multilayered thrombi. Both peptides phenotypically mimicked these changes, although they were less potent than CLB-RAg35. The second-round generation of an improved peptide, namely opt-mono-ORbIT (28 amino acids), showed an increased inhibitory activity under flow. Accordingly, our structure-based design of peptides resulted in physiologically effective peptide-based inhibitors, even for convoluted complexes such as GPIbα-VWF A1.

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“…MD simulations facilitate researchers to investigate the interactions of desired biological targets in terms of the binding energies at decreasing costs with advanced simulation methods ( Veselovsky and Ivanov, 2003 ; Aminpour et al, 2019 ). Moreover, molecular mechanics generalized born surface area (MM-GBSA) methods coupled with per-residue energy decomposition studies become the commonly used approaches computing the binding free energies, which could elucidate the energy contribution of each amino acid and aid for the rational drug design of desired targets ( Genheden and Ryde, 2015 ; Wichapong et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain

Tian

Yan

et al. 2022

Front. Mol. Biosci.

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Specific interaction between the postsynaptic density protein 95 (PSD95) and synapse-associated protein 90/postsynaptic density 95–associated protein (SAPAP) is crucial for excitatory synaptic development and plasticity. Designing inhibitors that target the guanylate kinase (GK) domain of PSD95, which is responsible for the interaction, is a promising manipulation tool for the investigation of the function of PSD95 GK and the etiology of its related psychiatric disorders. Herein, we designed new peptide inhibitors of PSD95 GK/SAPAP with higher binding affinity by using molecular dynamics simulations. First, the interactions between PSD95 GK and their reported phosphorylated and unphosphorylated peptides were explored by molecular dynamics simulations. Besides the hydrogen bonding interactions mediated by the phospho-serine (p-Ser) or corresponding phosphomimic residue Asp/Glu, the hydrophobic interactions from the other amino acids also contribute to the PSD95 GK/SAPAP interaction. As an unphosphorylated synthetic peptide with moderate binding affinity and relatively lower molecular weight, the QSF inhibitory peptide was selected for further modification. Based on per-residue energy decomposition results of the PSD95 GK/QSF complex, ten peptides were designed to enhance the binding interactions, especially the hydrophobic interactions. The top-ranked five peptides with lower binding energy were eventually synthesized. The binding affinities of the synthesized peptides were determined using fluorescence polarization (FP) assay. As expected, all peptides have higher binding affinity than the QSF peptide (Ki = 5.64 ± 0.51 μM). Among them, F10W was the most potent inhibitor (Ki = 0.75 ± 0.25 μM), suggesting that enhancement of the hydrophobic interactions is an important strategy for the design of new inhibitory peptides targeting PSD95 GK.

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Structure-based peptide design targeting intrinsically disordered proteins: Novel histone H4 and H2A peptidic inhibitors

Abstract: Graphical abstract

Cited by 22 publications

References 59 publications

The human disease geneCLEC16Aencodes an intrinsically disordered protein region required for mitochondrial quality control

The human disease geneCLEC16Aencodes an intrinsically disordered protein region required for mitochondrial quality control

Structure-Based Cyclic Glycoprotein Ibα-Derived Peptides Interfering with von Willebrand Factor-Binding, Affecting Platelet Aggregation under Shear

Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain

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