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Protein Structure–Function Relationships
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Protein Structure–Function Relationships

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 (25 April 2022) | Viewed by 17299

Special Issue Editor

Dr. Mohammad Hassan Baig

E-Mail
Guest Editor
Department of Family Medicine, Yonsei University College of Medicine, Seoul, Korea
Interests: biotechnology; R statistical package; bioinformatics; molecular biology; molecular dynamics; drug discovery; molecular dynamics simulation; computational chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins, the workhorses of the cell, essentially participate in all aspects of living systems. These biopolymers have always been the prime focus of extensive research, aiming to elucidate structure–function relationships. Proteins have a wide range of functions, including signal transduction, ion and nutrient transport, and various other essential processes required for the functioning of biological systems. Understanding the structure–function relationships of proteins is a hot topic, holding great importance in structural biology. The study of the impact of protein mutation, protein interaction with other proteins, and the binding of ligands on protein structure dynamics and function will help provide valuable insight. Besides, structural features are widely exploited in designing and developing small-molecule inhibitors targeting the therapeutic management of various life-threatening diseases. This Issue aims to invite articles focusing on structure–function relationships, drug discovery, evolutionary insights, and structural genomics using combined in silico and experimental methods.

Dr. Mohammad Hassan Baig
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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Keywords

Protein–protein interactions; Drug design; Molecular docking; Protein structural dynamics; Enzyme functions; QM/MM approaches; Virtual screening

Published Papers (5 papers)

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Research

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8 pages, 1947 KiB  
Article
Structural Aspects of E. coli Type II Asparaginase in Complex with Its Secondary Product L-Glutamate
by Maristella Maggi and Claudia Scotti
Int. J. Mol. Sci. 2022, 23(11), 5942; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115942 - 25 May 2022
Cited by 3 | Viewed by 1580
Abstract
Bacterial L-asparaginases are amidohydrolases (EC 3.5.1.1) capable of deaminating L-asparagine and, with reduced efficiency, L-glutamine. Interest in the study of L-asparaginases is driven by their use as biodrugs for the treatment of acute lymphoblastic leukemia. Here, we report for the first time the [...] Read more.
Bacterial L-asparaginases are amidohydrolases (EC 3.5.1.1) capable of deaminating L-asparagine and, with reduced efficiency, L-glutamine. Interest in the study of L-asparaginases is driven by their use as biodrugs for the treatment of acute lymphoblastic leukemia. Here, we report for the first time the description of the molecular structure of type II asparaginase from Escherichia coli in complex with its secondary product, L-glutamate. To obtain high-quality crystals, we took advantage of the N24S variant, which has structural and functional features similar to the wild-type enzyme, but improved stability, and which yields more ordered crystals. Analysis of the structure of the N24S-L–glutamate complex (N24S–GLU) and comparison with its apo and L-aspartate-bound form confirmed that the enzyme-reduced catalytic efficiency in the presence of L-glutamine is due to L-glutamine misfitting into the enzyme-binding pocket, which causes a local change in the catalytic center geometry. Moreover, a tight interaction between the two protomers that form the enzyme active site limits the capability of L-glutamine to fit into (and to exit from) the binding pocket of E. coli L-asparaginase, explaining why the enzyme has lower glutaminolytic activity compared to other enzymes of the same family, in particular the Erwinia chrysanthemi one. Full article
(This article belongs to the Special Issue Protein Structure–Function Relationships)
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11 pages, 1013 KiB  
Article
New Beta-lactamases in Candidate Phyla Radiation: Owning Pleiotropic Enzymes Is a Smart Paradigm for Microorganisms with a Reduced Genome
by Mohamad Maatouk, Ahmad Ibrahim, Lucile Pinault, Nicholas Armstrong, Said Azza, Jean-Marc Rolain, Fadi Bittar and Didier Raoult
Int. J. Mol. Sci. 2022, 23(10), 5446; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105446 - 13 May 2022
Cited by 6 | Viewed by 1857
Abstract
The increased exploitation of microbial sequencing methods has shed light on the high diversity of new microorganisms named Candidate Phyla Radiation (CPR). CPR are mainly detected via 16S rRNA/metabarcoding analyses or metagenomics and are found to be abundant in all environments and present [...] Read more.
The increased exploitation of microbial sequencing methods has shed light on the high diversity of new microorganisms named Candidate Phyla Radiation (CPR). CPR are mainly detected via 16S rRNA/metabarcoding analyses or metagenomics and are found to be abundant in all environments and present in different human microbiomes. These microbes, characterized by their symbiotic/epiparasitic lifestyle with bacteria, are directly exposed to competition with other microorganisms sharing the same ecological niche. Recently, a rich repertoire of enzymes with antibiotic resistance activity has been found in CPR genomes by using an in silico adapted screening strategy. This reservoir has shown a high prevalence of putative beta-lactamase-encoding genes. We expressed and purified five putative beta-lactamase sequences having the essential domains and functional motifs from class A and class B beta-lactamase. Their enzymatic activities were tested against various beta-lactam substrates using liquid chromatography-mass spectrometry (LC-MS) and showed some beta-lactamase activity even in the presence of a beta-lactamase inhibitor. In addition, ribonuclease activity was demonstrated against RNA that was not inhibited by sulbactam and EDTA. None of these proteins could degrade single- and double-stranded-DNA. This study is the first to express and test putative CPR beta-lactamase protein sequences in vitro. Our findings highlight that the reduced genomes of CPR members harbor sequences encoding for beta-lactamases known to be multifunction hydrolase enzymes. Full article
(This article belongs to the Special Issue Protein Structure–Function Relationships)
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24 pages, 4561 KiB  
Article
Demystifying DPP III Catalyzed Peptide Hydrolysis—Computational Study of the Complete Catalytic Cycle of Human DPP III Catalyzed Tynorphin Hydrolysis
by Antonija Tomić and Sanja Tomić
Int. J. Mol. Sci. 2022, 23(3), 1858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031858 - 06 Feb 2022
Cited by 5 | Viewed by 2043
Abstract
Dipeptidyl peptides III (DPP III) is a dual-domain zinc exopeptidase that hydrolyzes peptides of varying sequence and size. Despite attempts to elucidate and narrow down the broad substrate-specificity of DPP III, there is no explanation as to why some of them, such as [...] Read more.
Dipeptidyl peptides III (DPP III) is a dual-domain zinc exopeptidase that hydrolyzes peptides of varying sequence and size. Despite attempts to elucidate and narrow down the broad substrate-specificity of DPP III, there is no explanation as to why some of them, such as tynorphin (VVYPW), the truncated form of the endogenous heptapeptide spinorphin, are the slow-reacting substrates of DPP III compared to others, such as Leu-enkephalin. Using quantum molecular mechanics calculations followed by various molecular dynamics techniques, we describe for the first time the entire catalytic cycle of human DPP III, providing theoretical insight into the inhibitory mechanism of tynorphin. The chemical step of peptide bond hydrolysis and the substrate binding to the active site of the enzyme and release of the product were described for DPP III in complex with tynorphin and Leu-enkephalin and their products. We found that tynorphin is cleaved by the same reaction mechanism determined for Leu-enkephalin. More importantly, we showed that the product stabilization and regeneration of the enzyme, but not the nucleophilic attack of the catalytic water molecule and inversion at the nitrogen atom of the cleavable peptide bond, correspond to the rate-determining steps of the overall catalytic cycle of the enzyme. Full article
(This article belongs to the Special Issue Protein Structure–Function Relationships)
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15 pages, 3448 KiB  
Article
Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase
by Cynthia Fernández-Lainez, Ignacio de la Mora-de la Mora, Itzhel García-Torres, Sergio Enríquez-Flores, Luis A. Flores-López, Pedro Gutiérrez-Castrellón, Lilian Yépez-Mulia, Felix Matadamas-Martínez, Paul de Vos and Gabriel López-Velázquez
Int. J. Mol. Sci. 2021, 22(17), 9491; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179491 - 31 Aug 2021
Cited by 3 | Viewed by 5248
Abstract
Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we [...] Read more.
Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme’s structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman’s method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis. Full article
(This article belongs to the Special Issue Protein Structure–Function Relationships)
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Review

Jump to: Research

9 pages, 889 KiB  
Review
High Molecular Weight Kininogen: A Review of the Structural Literature
by Michał B. Ponczek
Int. J. Mol. Sci. 2021, 22(24), 13370; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413370 - 13 Dec 2021
Cited by 16 | Viewed by 4749
Abstract
Kininogens are multidomain glycoproteins found in the blood of most vertebrates. High molecular weight kininogen demonstrate both carrier and co-factor activity as part of the intrinsic pathway of coagulation, leading to thrombin generation. Kininogens are the source of the vasoactive nonapeptide bradykinin. To [...] Read more.
Kininogens are multidomain glycoproteins found in the blood of most vertebrates. High molecular weight kininogen demonstrate both carrier and co-factor activity as part of the intrinsic pathway of coagulation, leading to thrombin generation. Kininogens are the source of the vasoactive nonapeptide bradykinin. To date, attempts to crystallize kininogen have failed, and very little is known about the shape of kininogen at an atomic level. New advancements in the field of cryo-electron microscopy (cryoEM) have enabled researchers to crack the structure of proteins that has been refractory to traditional crystallography techniques. High molecular weight kininogen is a good candidate for structural investigation by cryoEM. The goal of this review is to summarize the findings of kininogen structural studies. Full article
(This article belongs to the Special Issue Protein Structure–Function Relationships)
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