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Protein-Peptide and Protein-Small Molecule Interactions

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 20397

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Special Issue Editor

Dr. Paolo Ruzza

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Guest Editor

Consiglio Nazionale delle Ricerche, Padua Unit, Rome, Italy
Interests: methods in biophysics; investigation of protein interactions by spectroscopic techniques; synthesis and conformational characterization of bioactive peptides; liquid chromatography; circular dichroism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is truly a great pleasure to put together a Special Issue on protein–peptide and protein–small molecule interactions. This important, exciting and timely topic has opened up new opportunities in drug discovery. Recently, different and innovative approaches have been developed to study these interactions, achieving important advancements of the basic sciences and medicinal chemistry. Chemists use small molecules (natural or synthetic products) as probes to identify possible therapeutically relevant protein targets. Biochemists and biologists seek to identify the endogenous metabolites that bind to specific proteins.

The purpose of this Special Issue is to attract the contribution of different researchers whose activity ranges from the development of biochemical and biophysical methods for detecting and measuring protein–peptide/small molecule interactions in vitro and in living cells, to the study of protein–ligand interfaces and the design of inhibitors, to conclude with computational approaches and internet resources for studying protein interactions.

Dr. Paolo Ruzza
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Protein-peptide interactions
Protein-small molecule interactions
Hotspot residues
Drug design

Published Papers (5 papers)

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Research

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21 pages, 5863 KiB

Open AccessArticle

Synthesis and Studies of the Inhibitory Effect of Hydroxylated Phenylpropanoids and Biphenols Derivatives on Tyrosinase and Laccase Enzymes

by Maria Antonietta Dettori, Davide Fabbri, Alessandro Dessì, Roberto Dallocchio, Paola Carta, Claudia Honisch, Paolo Ruzza, Donatella Farina, Rossana Migheli, Pier Andrea Serra, Roberto A. Pantaleoni, Xenia Fois, Gaia Rocchitta and Giovanna Delogu

Molecules 2020, 25(11), 2709; https://doi.org/10.3390/molecules25112709 - 11 Jun 2020

Cited by 12 | Viewed by 3325

Abstract

The impaired activity of tyrosinase and laccase can provoke serious concerns in the life cycles of mammals, insects and microorganisms. Investigation of inhibitors of these two enzymes may lead to the discovery of whitening agents, medicinal products, anti-browning substances and compounds for controlling harmful insects and bacteria. A small collection of novel reversible tyrosinase and laccase inhibitors with a phenylpropanoid and hydroxylated biphenyl core was prepared using naturally occurring compounds and their activity was measured by spectrophotometric and electrochemical assays. Biosensors based on tyrosinase and laccase enzymes were constructed and used to detect the type of protein-ligand interaction and half maximal inhibitory concentration (IC₅₀). Most of the inhibitors showed an IC₅₀ in a range of 20–423 nM for tyrosinase and 23–2619 nM for laccase. Due to the safety concerns of conventional tyrosinase and laccase inhibitors, the viability of the new compounds was assayed on PC12 cells, four of which showed a viability of roughly 80% at 40 µM. In silico studies on the crystal structure of laccase enzyme identified a hydroxylated biphenyl bearing a prenylated chain as the lead structure, which activated strong and effective interactions at the active site of the enzyme. These data were confirmed by in vivo experiments performed on the insect model Tenebrio molitur. Full article

(This article belongs to the Special Issue Protein-Peptide and Protein-Small Molecule Interactions)

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15 pages, 1815 KiB

Open AccessArticle

Membrane Phospholipids and Polyphosphates as Cofactors and Binding Molecules of SERPINA12 (vaspin)

by Catherine A. Tindall, Sebastian Dommel, Veronika Riedl, David Ulbricht, Stefanie Hanke, Norbert Sträter and John T. Heiker

Molecules 2020, 25(8), 1992; https://doi.org/10.3390/molecules25081992 - 24 Apr 2020

Cited by 4 | Viewed by 3401

Abstract

Visceral adipose tissue derived serine protease inhibitor (vaspin) is a member of the serpin family and has been shown to have beneficial effects on glucose tolerance, insulin stability as well as adipose tissue inflammation, parameters seriously affected by obesity. Some of these effects require inhibition of target proteases such as kallikrein 7(KLK7) and many studies have demonstrated vaspin-mediated activation of intracellular signaling cascades in various cells and tissues. So far, little is known about the exact mechanism how vaspin may trigger these intracellular signaling events. In this study, we investigated and characterized the interaction of vaspin with membrane lipids and polyphosphates as well as their potential regulatory effects on serpin activity using recombinant vaspin and KLK7 proteins and functional protein variants thereof. Here, we show for the first time that vaspin binds to phospholipids and polyphosphates with varying effects on KLK7 inhibition. Vaspin binds strongly to monophosphorylated phosphatidylinositol phosphates (PtdInsP) with no effect on vaspin activation. Microscale thermophoresis (MST) measurements revealed high-affinity binding to polyphosphate 45 (K_D: 466 ± 75 nM) and activation of vaspin in a heparin-like manner. Furthermore, we identified additional residues in the heparin binding site in β-sheet A by mutating five basic residues resulting in complete loss of high-affinity heparin binding. Finally, using lipid overlay assays, we show that these residues are additionally involved in PtdInsP binding. Phospholipids play a major role in membrane trafficking and signaling whereas polyphosphates are procoagulant and proinflammatory agents. The identification of phospholipids and polyphosphates as binding partners of vaspin will contribute to the understanding of vaspins involvement in membrane trafficking, signaling and beneficial effects associated with obesity. Full article

(This article belongs to the Special Issue Protein-Peptide and Protein-Small Molecule Interactions)

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16 pages, 2340 KiB

Open AccessArticle

The Secondary Structure of a Major Wine Protein is Modified upon Interaction with Polyphenols

by Mattia Di Gaspero, Paolo Ruzza, Rohanah Hussain, Claudia Honisch, Barbara Biondi, Giuliano Siligardi, Matteo Marangon, Andrea Curioni and Simone Vincenzi

Molecules 2020, 25(7), 1646; https://doi.org/10.3390/molecules25071646 - 03 Apr 2020

Cited by 18 | Viewed by 3924

Abstract

Polyphenols are an important constituent of wines and they are largely studied due to their antioxidant properties and for their effects on wine quality and stability, which is also related to their capacity to bind to proteins. The effects of some selected polyphenols, including procyanidins B1 and B2, tannic acid, quercetin, and rutin, as well as those of a total white wine procyanidin extract on the conformational properties of the major wine protein VVTL1 (Vitis vinifera Thaumatin-Like-1) were investigated by Synchrotron Radiation Circular Dichroism (SRCD). Results showed that VVTL1 interacts with polyphenols as demonstrated by the changes in the secondary (far-UV) and tertiary (near-UV) structures, which were differently affected by different polyphenols. Additionally, polyphenols modified the two melting temperatures (T_M) that were found for VVTL1 (32.2 °C and 53.9 °C for the protein alone). The circular dichroism (CD) spectra in the near-UV region revealed an involvement of the aromatic side-chains of the protein in the interaction with phenolics. The data demonstrate the existence of an interaction between polyphenols and VVTL1, which results in modification of its thermal and UV denaturation pattern. This information can be useful in understanding the behavior of wine proteins in presence of polyphenols, thus giving new insights on the phenomena that are involved in wine stability. Full article

(This article belongs to the Special Issue Protein-Peptide and Protein-Small Molecule Interactions)

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19 pages, 4428 KiB

Open AccessArticle

Evaluation of Isoflavones as Bone Resorption Inhibitors upon Interactions with Receptor Activator of Nuclear Factor-κB Ligand (RANKL)

by Małgorzata Zakłos-Szyda, Grażyna Budryn, Joanna Grzelczyk, Horacio Pérez-Sánchez and Dorota Żyżelewicz

Molecules 2020, 25(1), 206; https://doi.org/10.3390/molecules25010206 - 03 Jan 2020

Cited by 26 | Viewed by 4218

Abstract

Receptor activator of nuclear factor-κB ligand (RANKL) is a cytokine responsible for bone resorption. It binds its receptor RANK, which activates osteoporosis. High levels of osteoprotegerin (OPG) competitively binding RANKL limit formation of ligand-receptor complexes and enable bone mass maintenance. The new approach to prevent osteoporosis is searching for therapeutics that can bind RANKL and support OPG function. The aim of the study was to verify the hypothesis that isoflavones can form complexes with RANKL limiting binding of the cytokine to its receptor. Interactions of five isoflavones with RANKL were investigated by isothermal titration calorimetry (ITC), by in silico docking simulation and on Saos-2 cells. Daidzein and biochanin A showed the highest affinity for RANKL. Among studied isoflavones coumestrol, formononetin and biochanin A showed the highest potential for Saos-2 mineralization and were able to regulate the expression of RANKL and OPG at the mRNA levels, as well as osteogenic differentiation markers: alkaline phosphatase (ALP), collagen type 1, and Runt-related transcription factor 2 (Runx2). Comparison of the osteogenic activities of isoflavones showed that the use of physicochemical techniques such as ITC or in silico docking are good tools for the initial selection of substances showing a specific bioactivity. Full article

(This article belongs to the Special Issue Protein-Peptide and Protein-Small Molecule Interactions)

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Review

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41 pages, 1856 KiB

Open AccessReview

Capturing Peptide–GPCR Interactions and Their Dynamics

by Anette Kaiser and Irene Coin

Molecules 2020, 25(20), 4724; https://doi.org/10.3390/molecules25204724 - 15 Oct 2020

Cited by 22 | Viewed by 4852

Abstract

Many biological functions of peptides are mediated through G protein-coupled receptors (GPCRs). Upon ligand binding, GPCRs undergo conformational changes that facilitate the binding and activation of multiple effectors. GPCRs regulate nearly all physiological processes and are a favorite pharmacological target. In particular, drugs are sought after that elicit the recruitment of selected effectors only (biased ligands). Understanding how ligands bind to GPCRs and which conformational changes they induce is a fundamental step toward the development of more efficient and specific drugs. Moreover, it is emerging that the dynamic of the ligand–receptor interaction contributes to the specificity of both ligand recognition and effector recruitment, an aspect that is missing in structural snapshots from crystallography. We describe here biochemical and biophysical techniques to address ligand–receptor interactions in their structural and dynamic aspects, which include mutagenesis, crosslinking, spectroscopic techniques, and mass-spectrometry profiling. With a main focus on peptide receptors, we present methods to unveil the ligand–receptor contact interface and methods that address conformational changes both in the ligand and the GPCR. The presented studies highlight a wide structural heterogeneity among peptide receptors, reveal distinct structural changes occurring during ligand binding and a surprisingly high dynamics of the ligand–GPCR complexes. Full article

(This article belongs to the Special Issue Protein-Peptide and Protein-Small Molecule Interactions)

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