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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 39001

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Special Issue Editor

Dr. Jessica Holien

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Guest Editor

Biosciences and Food Technology, School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, VIC 3053, Australia
Interests: drug discovery; protein-protein interactions; structural bioinformatics; molecular modelling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There are over 300,000 protein–protein interaction (PPI) pairs identified in the human genome. Thus, it is not surprising that modulators of PPIs—ideally small “drug-like” molecules—are urgently being sought and developed by the pharmaceutical Industry to treat unmet medical need. However, the physical characteristics of the PPI interface make this task nontrivial. Futhermore, unlike the traditional pharmaceutical approach of focusing on finding a ‘single switch that works’, it is clear that the phenotype of many diseases relies on complex networks of PPIs. Destabilising these networks for a successful therapeutic approach will require perturbing multiple key interactions.

This Special Issue focusses on recent studies aiming to investigate protien–protein interactions, with an additional aim of developing drugs to modulate these interactions. Specifically, this issue will explore the latest computational and structural biology methods, and studies which further our understanding of protein–protien interfaces and of how to better develop molecules to modulate these are welcomed.

Dr. Jessica Holien
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

protein–protein interactions
structural biology
bioinformatics
network analysis
drug design
drug development
computational drug design
protein–ligand interactions
target identification

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Related Special Issue

Advances in Protein-Protein Interactions—2nd Edition in International Journal of Molecular Sciences (8 articles)

Published Papers (11 papers)

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Research

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14 pages, 3020 KiB

Open AccessArticle

Blue Native PAGE–Antibody Shift in Conjunction with Mass Spectrometry to Reveal Protein Subcomplexes: Detection of a Cerebellar α1/α6-Subunits Containing γ-Aminobutyric Acid Type A Receptor Subtype

by Miao Chen, Frank Koopmans, Iryna Paliukhovich, Sophie J. F. van der Spek, Jian Dong, August B. Smit and Ka Wan Li

Int. J. Mol. Sci. 2023, 24(8), 7632; https://doi.org/10.3390/ijms24087632 - 21 Apr 2023

Cited by 3 | Viewed by 2121

Abstract

The pentameric γ-Aminobutyric acid type A receptors (GABA_ARs) are ligand-gated ion channels that mediate the majority of inhibitory neurotransmission in the brain. In the cerebellum, the two main receptor subtypes are the 2α1/2β/γ and 2α6/2β/δ subunits. In the present study, an interaction proteomics workflow was used to reveal additional subtypes that contain both α1 and α6 subunits. Immunoprecipitation of the α6 subunit from mouse brain cerebellar extract co-purified the α1 subunit. In line with this, pre-incubation of the cerebellar extract with anti-α6 antibodies and analysis by blue native gel electrophoresis mass-shifted part of the α1 complexes, indicative of the existence of an α1α6-containing receptor. Subsequent mass spectrometry of the blue native gel showed the α1α6-containing receptor subtype to exist in two main forms, i.e., with or without Neuroligin-2. Immunocytochemistry on a cerebellar granule cell culture revealed co-localization of α6 and α1 in post-synaptic puncta that apposed the presynaptic marker protein Vesicular GABA transporter, indicative of the presence of this synaptic GABA_AR subtype. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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16 pages, 2255 KiB

Open AccessArticle

Analysis of the Genetic Relationship between Atherosclerosis and Non-Alcoholic Fatty Liver Disease through Biological Interaction Networks

by Francisco Andújar-Vera, María Ferrer-Millán, Cristina García-Fontana, Beatriz García-Fontana, Sheila González-Salvatierra, Raquel Sanabria-de la Torre, Luis Martínez-Heredia, Blanca Riquelme-Gallego and Manuel Muñoz-Torres

Int. J. Mol. Sci. 2023, 24(4), 4124; https://doi.org/10.3390/ijms24044124 - 18 Feb 2023

Cited by 4 | Viewed by 2602

Abstract

Non-alcoholic fatty liver disease (NAFLD) seems to have some molecular links with atherosclerosis (ATH); however, the molecular pathways which connect both pathologies remain unexplored to date. The identification of common factors is of great interest to explore some therapeutic strategies to improve the outcomes for those affected patients. Differentially expressed genes (DEGs) for NAFLD and ATH were extracted from the GSE89632 and GSE100927 datasets, and common up- and downregulated DEGs were identified. Subsequently, a protein–protein interaction (PPI) network based on the common DEGs was performed. Functional modules were identified, and the hub genes were extracted. Then, a Gene Ontology (GO) and pathway analysis of common DEGs was performed. DEGs analysis in NAFLD and ATH showed 21 genes that were regulated similarly in both pathologies. The common DEGs with high centrality scores were ADAMTS1 and CEBPA which appeared to be down- and up-regulated in both disorders, respectively. For the analysis of functional modules, two modules were identified. The first one was oriented to post-translational protein modification, where ADAMTS1 and ADAMTS4 were identified, and the second one mainly related to the immune response, where CSF3 was identified. These factors could be key proteins with an important role in the NAFLD/ATH axis. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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12 pages, 3818 KiB

Open AccessArticle

Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

by Xuanyan Jia, Leishu Lin, Shun Xu, Lingxuan Li, Zhiyi Wei, Cong Yu and Fengfeng Niu

Int. J. Mol. Sci. 2023, 24(2), 1414; https://doi.org/10.3390/ijms24021414 - 11 Jan 2023

Cited by 5 | Viewed by 2757

Abstract

SH3 domains are common protein binding modules. The target sequence of SH3 domains is usually a proline-rich motif (PRM) containing a minimal “PxxP” sequence. The mechanism of how different SH3 domains specifically choose their targets from vast PxxP-containing sequences is still not very clear, as many reported SH3/PRM interactions are weak and promiscuous. Here, we identified the binding of the SH3 domain of ASAP1 to the PRM of MICAL1 with a sub-μM binding affinity, and determined the crystal structure of ASAP1-SH3 and MICAL1-PRM complex. Our structural and biochemical analyses revealed that the target-binding pocket of ASAP1-SH3 contains two negatively charged patches to recognize the “xPx + Px+” sequence in MICAL1-PRM and consequently strengthen the interaction, differing from the typical SH3/PRM interaction. This unique PRM-binding pocket is also found in the SH3 domains of GTPase Regulator associated with focal adhesion kinase (GRAF) and Src kinase associated phosphoprotein 1 (SKAP1), which we named SH3^AGS. In addition, we searched the Swiss-Prot database and found ~130 proteins with the SH3^AGS-binding PRM in silico. Finally, gene ontology analysis suggests that the strong interaction between the SH3^AGS-containing proteins and their targets may play roles in actin cytoskeleton regulation and vesicle trafficking. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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25 pages, 3474 KiB

Open AccessArticle

Split-GFP Reassembly Assay: Strengths and Caveats from a Multiparametric Analysis

by Christophe Bignon, Antoine Gruet and Sonia Longhi

Int. J. Mol. Sci. 2022, 23(21), 13167; https://doi.org/10.3390/ijms232113167 - 29 Oct 2022

Cited by 3 | Viewed by 4113

Abstract

The split-Green Fluorescent Protein (GFP) reassembly assay is a powerful approach to study protein–protein interactions (PPIs). In this assay, two proteins, respectively, fused to the first seven and the last four β-strands of GFP are co-expressed in E. coli where they can bind to each other, which reconstitutes the full-length GFP. Thus, the fluorescence of the bacteria co-expressing the two fusion proteins accounts for the interaction of the two proteins of interest. The first split-GFP reassembly assay was devised in the early 2000s in Regan’s lab. During the last ten years, we have been extensively using this assay to study the interactions of an intrinsically disordered protein (IDP) with two globular partners. Over that period, in addition to accumulating molecular information on the specific interactions under study, we progressively modified the original technique and tested various parameters. In those previous studies, however, we focused on the mechanistic insights provided by the approach, rather than on the method itself. Since methodological aspects deserve attention and the best bipartite reporter to study PPIs involving IDPs remains to be identified, we herein focus on technical aspects. To this end, we first revisit our previous modifications of the original method and then investigate the impact of a panel of additional parameters. The present study unveiled a few critical parameters that deserve consideration to avoid pitfalls and obtain reliable results. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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17 pages, 2962 KiB

Open AccessArticle

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

by Anne V. Yagolovich, Alina A. Isakova, Artem A. Artykov, Yekaterina V. Vorontsova, Diana V. Mazur, Nadezhda V. Antipova, Marat S. Pavlyukov, Mikhail I. Shakhparonov, Anastasia M. Gileva, Elena A. Markvicheva, Ekaterina A. Plotnikova, Andrey A. Pankratov, Mikhail P. Kirpichnikov, Marine E. Gasparian and Dmitry A. Dolgikh

Int. J. Mol. Sci. 2022, 23(20), 12687; https://doi.org/10.3390/ijms232012687 - 21 Oct 2022

Cited by 5 | Viewed by 2473 | Correction

Abstract

TRAIL (TNF-related apoptosis-inducing ligand) and its derivatives are potentials for anticancer therapy due to the selective induction of apoptosis in tumor cells upon binding to death receptors DR4 or DR5. Previously, we generated a DR5-selective TRAIL mutant variant DR5-B overcoming receptor-dependent resistance of tumor cells to TRAIL. In the current study, we improved the antitumor activity of DR5-B by fusion with a tumor-homing iRGD peptide, which is known to enhance the drug penetration into tumor tissues. The obtained bispecific fusion protein DR5-B-iRGD exhibited dual affinity for DR5 and integrin αvβ3 receptors. DR5-B-iRGD penetrated into U-87 tumor spheroids faster than DR5-B and demonstrated an enhanced antitumor effect in human glioblastoma cell lines T98G and U-87, as well as in primary patient-derived glioblastoma neurospheres in vitro. Additionally, DR5-B-iRGD was highly effective in a xenograft mouse model of the U-87 human glioblastoma cell line in vivo. We suggest that DR5-B-iRGD may become a promising candidate for targeted therapy for glioblastoma. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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19 pages, 6011 KiB

Open AccessArticle

Network-Pharmacology-Based Study on Active Phytochemicals and Molecular Mechanism of Cnidium monnieri in Treating Hepatocellular Carcinoma

by Shakeel Ahmad Khan and Terence Kin Wah Lee

Int. J. Mol. Sci. 2022, 23(10), 5400; https://doi.org/10.3390/ijms23105400 - 12 May 2022

Cited by 15 | Viewed by 3942

Abstract

Hepatocellular carcinoma (HCC) is a malignancy with a high mortality rate globally. For thousands of years, Cnidium monnieri has been used to treat human ailments and is regarded as a veritable treasure trove for drug discovery. This study has investigated the key active phytochemicals and molecular mechanisms of Cnidium monnieri implicated in curing HCC. We utilized the TCMSP database to collect data on the phytochemicals of Cnidium monnieri. The SwissTargetPrediction website tool was used to predict the targets of phytochemicals of Cnidium monnieri. HCC-related genes were retrieved from OncoDB.HCC and Liverome, two liver-cancer-related databases. Using the DAVID bioinformatic website tool, Gene Ontology (GO) and KEGG enrichment analysis were performed on the intersecting targets of HCC-related genes and active phytochemicals in Cnidium monnieri. A network of active phytochemicals and anti-HCC targets was constructed and analyzed using Cytoscape software. Molecular docking of key active phytochemicals was performed with anti-HCC targets using AutoDock Vina (version 1.2.0.). We identified 19 active phytochemicals in Cnidium monnieri, 532 potential targets of these phytochemicals, and 566 HCC-related genes. Results of GO enrichment indicated that Cnidium monnieri might be implicated in affecting gene targets involved in multiple biological processes, such as protein phosphorylation, negative regulation of the apoptotic process, which could be attributed to its anti-HCC effects. KEGG pathway analyses indicated that the PI3K–AKT signaling pathway, pathways in cancer, proteoglycans in cancer, the TNF signaling pathway, VEGF signaling pathway, ErbB signaling pathway, and EGFR tyrosine kinase inhibitor resistance are the main pathways implicated in the anti-HCC effects of Cnidium monnieri. Molecular docking analyses showed that key active phytochemicals of Cnidium monnieri, such as ar-curcumene, diosmetin, and (E)-2,3-bis(2-keto-7-methoxy-chromen-8-yl)acrolein, can bind to core therapeutic targets EGFR, CASP3, ESR1, MAPK3, CCND1, and ERBB2. The results of the present study offer clues for further investigation of the anti-HCC phytochemicals and mechanisms of Cnidium monnieri and provide a basis for developing modern anti-HCC drugs based on phytochemicals in Cnidium monnieri. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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19 pages, 4859 KiB

Open AccessArticle

BRET Analysis of GPCR Dimers in Neurons and Non-Neuronal Cells: Evidence for Inactive, Agonist, and Constitutive Conformations

by Chayma El Khamlichi, Laetitia Cobret, Jean-Michel Arrang and Séverine Morisset-Lopez

Int. J. Mol. Sci. 2021, 22(19), 10638; https://doi.org/10.3390/ijms221910638 - 30 Sep 2021

Cited by 4 | Viewed by 4173

Abstract

G-protein-coupled receptors (GPCRs) are dimeric proteins, but the functional consequences of the process are still debated. Active GPCR conformations are promoted either by agonists or constitutive activity. Inverse agonists decrease constitutive activity by promoting inactive conformations. The histamine H₃ receptor (H₃R) is the target of choice for the study of GPCRs because it displays high constitutive activity. Here, we study the dimerization of recombinant and brain H₃R and explore the effects of H₃R ligands of different intrinsic efficacy on dimerization. Co-immunoprecipitations and Western blots showed that H₃R dimers co-exist with monomers in transfected HEK 293 cells and in rodent brains. Bioluminescence energy transfer (BRET) analysis confirmed the existence of spontaneous H₃R dimers, not only in living HEK 293 cells but also in transfected cortical neurons. In both cells, agonists and constitutive activity of the H₃R decreased BRET signals, whereas inverse agonists and GTPγS, which promote inactive conformations, increased BRET signals. These findings show the existence of spontaneous H₃R dimers not only in heterologous systems but also in native tissues, which are able to adopt a number of allosteric conformations, from more inactive to more active states. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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27 pages, 12072 KiB

Open AccessArticle

Network Pharmacology Study on Morus alba L. Leaves: Pivotal Functions of Bioactives on RAS Signaling Pathway and Its Associated Target Proteins against Gout

by Ki Kwang Oh, Md. Adnan and Dong Ha Cho

Int. J. Mol. Sci. 2021, 22(17), 9372; https://doi.org/10.3390/ijms22179372 - 29 Aug 2021

Cited by 13 | Viewed by 4152

Abstract

M. alba L. is a valuable nutraceutical plant rich in potential bioactive compounds with promising anti-gouty arthritis. Here, we have explored bioactives, signaling pathways, and key proteins underlying the anti-gout activity of M. alba L. leaves for the first-time utilizing network pharmacology. Bioactives in M. alba L. leaves were detected through GC-MS (Gas Chromatography-Mass Spectrum) analysis and filtered by Lipinski’s rule. Target proteins connected to the filtered compounds and gout were selected from public databases. The overlapping target proteins between bioactives-interacted target proteins and gout-targeted proteins were identified using a Venn diagram. Bioactives-Proteins interactive networking for gout was analyzed to identify potential ligand-target and visualized the rich factor on the R package via the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on STRING. Finally, a molecular docking test (MDT) between bioactives and target proteins was analyzed via AutoDock Vina. Gene Set Enrichment Analysis (GSEA) demonstrated that mechanisms of M. alba L. leaves against gout were connected to 17 signaling pathways on 26 compounds. AKT1 (AKT Serine/Threonine Kinase 1), γ-Tocopherol, and RAS signaling pathway were selected as a hub target, a key bioactive, and a hub signaling pathway, respectively. Furthermore, three main compounds (γ-Tocopherol, 4-Dehydroxy-N-(4,5-methylenedioxy-2-nitrobenzylidene) tyramine, and Lanosterol acetate) and three key target proteins—AKT1, PRKCA, and PLA2G2A associated with the RAS signaling pathway were noted for their highest affinity on MDT. The identified three key bioactives in M. alba L. leaves might contribute to recovering gouty condition by inactivating the RAS signaling pathway. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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Review

Jump to: Research, Other

23 pages, 2482 KiB

Open AccessReview

SH2 Domains: Folding, Binding and Therapeutical Approaches

by Awa Diop, Daniele Santorelli, Francesca Malagrinò, Caterina Nardella, Valeria Pennacchietti, Livia Pagano, Lucia Marcocci, Paola Pietrangeli, Stefano Gianni and Angelo Toto

Int. J. Mol. Sci. 2022, 23(24), 15944; https://doi.org/10.3390/ijms232415944 - 15 Dec 2022

Cited by 20 | Viewed by 6164

Abstract

SH2 (Src Homology 2) domains are among the best characterized and most studied protein-protein interaction (PPIs) modules able to bind and recognize sequences presenting a phosphorylated tyrosine. This post-translational modification is a key regulator of a plethora of physiological and molecular pathways in the eukaryotic cell, so SH2 domains possess a fundamental role in cell signaling. Consequently, several pathologies arise from the dysregulation of such SH2-domains mediated PPIs. In this review, we recapitulate the current knowledge about the structural, folding stability, and binding properties of SH2 domains and their roles in molecular pathways and pathogenesis. Moreover, we focus attention on the different strategies employed to modulate/inhibit SH2 domains binding. Altogether, the information gathered points to evidence that pharmacological interest in SH2 domains is highly strategic to developing new therapeutics. Moreover, a deeper understanding of the molecular determinants of the thermodynamic stability as well as of the binding properties of SH2 domains appears to be fundamental in order to improve the possibility of preventing their dysregulated interactions. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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25 pages, 3428 KiB

Open AccessReview

Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models

by Igor Sedov and Diliara Khaibrakhmanova

Int. J. Mol. Sci. 2022, 23(21), 13428; https://doi.org/10.3390/ijms232113428 - 3 Nov 2022

Cited by 20 | Viewed by 4068

Abstract

Inhibition of fibril formation is considered a possible treatment strategy for amyloid-related diseases. Understanding the molecular nature of inhibitor action is crucial for the design of drug candidates. In the present review, we describe the common kinetic models of fibril formation and classify known inhibitors by the mechanism of their interactions with the aggregating protein and its oligomers. This mechanism determines the step or steps of the aggregation process that become inhibited and the observed changes in kinetics and equilibrium of fibril formation. The results of numerous studies indicate that possible approaches to antiamyloid inhibitor discovery include the search for the strong binders of protein monomers, cappers blocking the ends of the growing fibril, or the species absorbing on the surface of oligomers preventing nucleation. Strongly binding inhibitors stabilizing the native state can be promising for the structured proteins while designing the drug candidates targeting disordered proteins is challenging. Full article

(This article belongs to the Special Issue Advances in Protein-Protein Interactions)

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