Molecular insights on the coronavirus MERS-CoV interaction with the CD26 receptor.

The Middle East respiratory syndrome (MERS) is a severe respiratory disease with high fatality rates, caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). The virus initiates infection by binding to the CD26 receptor (also known as dipeptidyl peptidase 4 or DPP4) via its spike protein. Although the receptor-binding domain (RBD) of the viral spike protein and the complex between RBD and the extracellular domain of CD26 have been studied using X-ray crystallography, conflicting studies exist regarding the importance of certain amino acids outside the resolved RBD-CD26 complex interaction interface.

Cytotoxicity and reversal effect of sertraline, fluoxetine, and citalopram on MRP1- and MRP7-mediated MDR.

Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent years, researchers have focused on understanding the mechanisms of multidrug resistance (MDR) in cancer cells and have identified the overexpression of ATP-binding cassette (ABC) transporters, including ABCC1/MRP1 and ABCC10/MRP7, as a key factor in the development of MDR. In this study, we aimed to investigate whether three drugs (sertraline, fluoxetine, and citalopram) from the selective serotonin reuptake inhibitor (SSRI) family, commonly used as antidepressants, could be repurposed as inhibitors of MRP1 and MRP7 transporters and reverse MDR in cancer cells.

Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1).

Dynamic conformational changes play a major role in the function of proteins, including the ATP-Binding Cassette (ABC) transporters. Multidrug Resistance Protein 1 (MRP1) is an ABC exporter that protects cells from toxic molecules. Overexpression of MRP1 has been shown to confer Multidrug Resistance (MDR), a phenomenon in which cancer cells are capable to defend themselves against a broad variety of drugs.

From virus to diabetes therapy: Characterization of a specific insulin-degrading enzyme inhibitor for diabetes treatment.

Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor.

Correction: Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter.

[This corrects the article DOI: 10.1371/journal.pcbi.

Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter.

Multiscale modeling provides a very powerful means of studying complex biological systems. An important component of this strategy involves coarse-grained (CG) simplifications of regions of the system, which allow effective exploration of complex systems. Here we studied aspects of CG modeling of the human zinc transporter ZnT2.

The involvement of coordinative interactions in the binding of dihydrolipoamide dehydrogenase to titanium dioxide-Localization of a putative binding site.

Titanium (Ti) and its alloys are widely used in orthodontic and orthopedic implants by virtue to their high biocompatibility, mechanical strength, and high resistance to corrosion. Biointegration of the implants with the tissue requires strong interactions, which involve biological molecules, proteins in particular, with metal oxide surfaces. An exocellular high-affinity titanium dioxide (TiO )-binding protein (TiBP), purified from Rhodococcus ruber, has been previously studied in our lab.

Mechanistic studies of the apical sodium-dependent bile acid transporter.

In mammals, the apical sodium-dependent bile acid transporter (ASBT) is responsible for the reuptake of bile acid from the intestine, thus recycling bile acid that is secreted from the gallbladder, for the purpose of digestion. As bile acid is synthesized from cholesterol, ASBT inhibition could have important implications in regulation of cholesterol levels in the blood. We report on a simulation study of the recently resolved structures of the inward-facing ASBT from Neisseria meningitidis and from Yersinia frederiksenii, as well as of an ASBT variant from Yersinia frederiksenii suggested to be in the outward-facing conformation.

Overcoming multidrug resistance with nanomedicines.

Introduction: Cancer remains the leading cause of death worldwide. Numerous therapeutic strategies that include smart biological treatments toward specific cellular pathways are being developed. Yet, inherent and acquired multidrug resistance (MDR) to chemotherapeutic drugs remains the major obstacle in effective cancer treatments.

Acetylation of lysine 382 and phosphorylation of serine 392 in p53 modulate the interaction between p53 and MDC1 in vitro.

Occurrence of DNA damage in a cell activates the DNA damage response, a survival mechanism that ensures genomics stability. Two key members of the DNA damage response are the tumor suppressor p53, which is the most frequently mutated gene in cancers, and MDC1, which is a central adaptor that recruits many proteins to sites of DNA damage. Here we characterize the in vitro interaction between p53 and MDC1 and demonstrate that p53 and MDC1 directly interact.

Ubiquitin: molecular modeling and simulations.

The synthesis and destruction of proteins are imperative for maintaining their cellular homeostasis. In the 1970s, Aaron Ciechanover, Avram Hershko, and Irwin Rose discovered that certain proteins are tagged by ubiquitin before degradation, a discovery that awarded them the 2004 Nobel Prize in Chemistry. Compelling data gathered during the last several decades show that ubiquitin plays a vital role not only in protein degradation but also in many cellular functions including DNA repair processes, cell cycle regulation, cell growth, immune system functionality, hormone-mediated signaling in plants, vesicular trafficking pathways, regulation of histone modification and viral budding.

Characterization of the Na⁺/H⁺ antiporter from Yersinia pestis.

Yersinia pestis, the bacterium that historically accounts for the Black Death epidemics, has nowadays gained new attention as a possible biological warfare agent. In this study, its Na⁺/H⁺ antiporter is investigated for the first time, by a combination of experimental and computational methodologies. We determined the protein's substrate specificity and pH dependence by fluorescence measurements in everted membrane vesicles.

Promiscuous binding in a selective protein: the bacterial Na+/H+ antiporter.

The ability to discriminate between highly similar substrates is one of the remarkable properties of enzymes. For example, transporters and channels that selectively distinguish between various solutes enable living organisms to maintain and control their internal environment in the face of a constantly changing surrounding. Herein, we examine in detail the selectivity properties of one of the most important salt transporters: the bacterial Na+/H+ antiporter.

Computational study of the Na+/H + antiporter from Vibrio parahaemolyticus.

Sodium proton antiporters are ubiquitous membrane proteins that catalyze the exchange of Na(+) for protons throughout the biological world. The Escherichia coli NhaA is the archetypal Na(+)/H(+) antiporter and is absolutely essential for survival in high salt concentrations under alkaline conditions. Its crystal structure, accompanied by extensive molecular dynamics simulations, have provided an atomically detailed model of its mechanism.

Insight into the interaction sites between fatty acid binding proteins and their ligands.

Fatty acid binding proteins (FABPs), are evolutionarily conserved small cytoplasmic proteins that occur in many tissue-specific types. One of their primary functions is to facilitate the clearance of the cytoplasmic matrix from free fatty acids and of other detergent-like compounds. Crystallographic studies of FABP proteins have revealed a well defined binding site located deep inside their beta-clam structure that is hardly exposed to the bulk solution.

Myosin V movement: lessons from molecular dynamics studies of IQ peptides in the lever arm.

Myosin V moves along actin filaments by an arm-over-arm motion, known as the lever mechanism. Each of its arms is composed of six consecutive IQ peptides that bind light chain proteins, such as calmodulin or calmodulin-like proteins. We have employed a multistage approach in order to investigate the mechanochemical structural basis of the movement of myosin V from the budding yeast Saccharomyces cerevisiae.

A molecular dynamics study and free energy analysis of complexes between the Mlc1p protein and two IQ motif peptides.

The Mlc1p protein from the budding yeast Saccharomyces cerevisiae is a Calmodulin-like protein, which interacts with IQ-motif peptides located at the yeast's myosin neck. In this study, we report a molecular dynamics study of the Mlc1p-IQ2 protein-peptide complex, starting with its crystal structure, and investigate its dynamics in an aqueous solution. The results are compared with those obtained by a previous study, where we followed the solution structure of the Mlc1p-IQ4 protein-peptide complex by molecular dynamics simulations.

Molecular dynamics study of a calmodulin-like protein with an IQ peptide: spontaneous refolding of the protein around the peptide.

The Calmodulin (CaM) is a small (16.7 kDa), highly acidic protein that is crucial to all eukaryotes by serving as a prototypical calcium sensor. In the present study, we investigated, through molecular dynamics simulations, the dynamics of a complex between the Mlc1p protein, which is a CaM-like protein, and the IQ4 peptide.