Rational Design of an Orthogonal Molecular Interaction System at the Complex Interface of Lung Cancer-Related MDM2 Protein with p53 Peptide

2016 ◽  
Vol 69 (10) ◽  
pp. 1167 ◽  
Author(s):  
Yanwen Li ◽  
Xiyan Yu ◽  
Ying Lou ◽  
Tong Wang
Keyword(s):  
Lung Cancer ◽  
Molecular Interaction ◽  
Rational Design ◽  
Halogen Atom ◽  
Halogen Bond ◽  
Negative Control ◽  
Negative Regulator ◽  
Transactivation Domain ◽  
Interaction System ◽  
Oncogenic Protein

The oncogenic protein MDM2 is an important negative regulator of p53 tumour suppressor. Overexpression of this protein is closely related to the pathological progression and metastasis of lung cancer and other tumours. Previously, a 12-mer peptide segment 17ETFSDLWKLLPE28 (p5317–28) corresponding to residues 17–28 of the human p53 transactivation domain was identified to interact moderately with MDM2. Here, we successfully created an orthogonal molecular interaction system between a native hydrogen bond (H-bond) and a designed halogen bond (X-bond) across the protein–peptide complex interface, where the X-bond was introduced by substituting the 3-hydrogen atom of the benzene ring of the p5317–28 Phe19 residue with a halogen atom X, resulting in a series of 3X-peptides (X = F, Cl, Br or I). Theoretical analysis found that chlorine is a good compromise between X-bonding strength and steric hindrance due to introducing a bulkier halogen atom to the tightly packed complex interface. Consequently, the 3Cl-peptide (Kd = 105 nM) was determined to exhibit ~5-fold affinity improvement relative to p5317–28 (Kd = 570 nM). In contrast, the binding affinity of the 2Cl-peptide (Kd = 492 nM), a negative control that cannot form the X-bond according to computational analysis, did not change considerably on the halogenation.

Rational design of an orthogonal noncovalent interaction system at the MUPP1 PDZ11 complex interface with CaMKIIα-derived peptides in human fertilization

2017 ◽  
Vol 13 (10) ◽  
pp. 2145-2151 ◽  
Author(s):  
Yi-Le Zhang ◽  
Zhao-Feng Han
Keyword(s):  
Hydrogen Bond ◽  
Rational Design ◽  
Halogen Bond ◽  
Noncovalent Interaction ◽  
Rational Approach ◽  
Interaction System ◽  
Human Fertilization

An orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of the MUPP1 PDZ11 domain with the CaMKIIαsia[Asn-1Phe] peptide mutant is introduced using a structure-based rational approach.

Cyclic networks of halogen-bonding interactions in molecular self-assemblies: a theoretical N—X...NversusC—X...N investigation

2017 ◽  
Vol 73 (2) ◽  
pp. 179-187
Author(s):  
Ruben D. Parra ◽  
Álvaro Castillo
Keyword(s):  
Electron Density ◽  
Self Assembly ◽  
Metal Ion ◽  
Halogen Atom ◽  
Halogen Bond ◽  
Halogen Bonding ◽  
Nbo Analysis ◽  
Binding Energies ◽  
Cyclic Network ◽  
Ability To Drive

The geometries and energetics of molecular self-assembly structures that contain a sequential network of cyclic halogen-bonding interactions are investigated theoretically. The strength of the halogen-bonding interactions is assessed by examining binding energies, electron charge transfer (NBO analysis) and electron density at halogen-bond critical points (AIM theory). Specifically, structural motifs having intramolecular N—X...N (X= Cl, Br, or I) interactions and the ability to drive molecular self-assemblyviathe same type of interactions are used to construct larger self-assemblies of up to three unit motifs. N—X...N halogen-bond cooperativity as a function of the self-assembly size, and the nature of the halogen atom is also examined. The cyclic network of the halogen-bonding interactions provides a suitable cavity rich in electron density (from the halogen atom lone pairs not involved in the halogen bonds) that can potentially bind an electron-deficient species such as a metal ion. This possibility is explored by examining the ability of the N—X...N network to bind Na+. Likewise, molecular self-assembly structures driven by the weaker C—X...N halogen-bonding interactions are investigated and the results compared with those of their N—X...N counterparts.

scholarly journals Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2213 ◽  
Author(s):  
Alessandro Dessì ◽  
Paola Peluso ◽  
Roberto Dallocchio ◽  
Robin Weiss ◽  
Giuseppina Andreotti ◽  
...  
Keyword(s):  
High Performance ◽  
Rational Design ◽  
Halogen Bond ◽  
Coupling Reaction ◽  
Docking Studies ◽  
Binding Modes ◽  
Design Synthesis ◽  
In Silico Docking ◽  
Amyloid Fibril Formation ◽  
The Right

The 3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3′,5,5′-tetrachloro-2-iodo-2′-substituted-4,4′- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2′-substituent. The corresponding racemates, along with other five chiral 4,4′-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4′-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3′,5,5′-tetrachloro-2′-(4-hydroxyphenyl)-2-iodo-4,4′-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4′-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4′-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

YAP mediates the positive regulation of hnRNPK on the lung adenocarcinoma H1299 cell growth

2019 ◽  
Vol 51 (7) ◽  
pp. 677-687
Author(s):  
Lipei Xu ◽  
Tingting Zhang ◽  
Wensi Huang ◽  
Xiaohui Liu ◽  
Junlei Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Contact Inhibition ◽  
Negative Regulator ◽  
Cell Contact ◽  
Reporter System ◽  
H1299 Cell ◽  
Multifunctional Protein

AbstractLung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) accounts for 80%–85% of diagnostic cases. The molecular mechanisms of NSCLC pathogenesis are not well understood. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a multifunctional protein that regulates gene expression and signal transduction and closely associated with tumorigenesis, but its mechanism of action in the pathogenesis of NSCLC is unclear. In this study, we observed that the expression pattern of hnRNPK in H1299 lung adenocarcinoma cells varied depending on the cell density in culture. Moreover, hnRNPK stimulated the ability of proliferation and colony formation of H1299 cells, which is important for the multilayered cell growth in culture. We further investigated whether there is an association between hnRNPK and the elements involved in the cell contact inhibition pathway. By using quantitative reverse transcriptase-polymerase chain reaction assay and a YAP activity reporter system, we found that hnRNPK upregulated the mRNA and protein levels and transcriptional activity of Yes-associated protein 1 (YAP), a master negative regulator of Hippo contact inhibition pathway. Furthermore, YAP knockdown with siRNA abolished the stimulatory effect of hnRNPK on H1299 cell proliferation. These results suggested that YAP could be one of the effectors of hnRNPK. Our data may provide new clues for further understanding the biological functions of hnRNPK, particularly in the context of lung adenocarcinoma oncogenesis.

scholarly journals Possible Molecular Mechanisms for the Roles of MicroRNA-21 Played in Lung Cancer

2019 ◽  
Vol 18 ◽  
pp. 153303381987513 ◽  
Author(s):  
Qiang Wang ◽  
Linyou Zhang
Keyword(s):  
Lung Cancer ◽  
Transcription Factor ◽  
Cell Division ◽  
A549 Cells ◽  
Group Versus ◽  
Negative Control ◽  
Replication Initiation ◽  
Cell Division Cycle ◽  
Initiation Factor ◽  
Control Group

Background: We aimed to find the possible molecular mechanisms for the roles of microRNA-21 underlying lung cancer development. Methods: MicroRNA-21-5p inhibitor was transfected into A549 cells. Total RNA was isolated from 10 samples, including 3 in control group (A549 cells), 3 in negative control group (A549 cells transferred with microRNA-21 negative control), and 4 in SH group (A549 cells transferred with microRNA-21 inhibitor), followed by RNA sequencing. Then, differentially expressed genes were screened for negative control group versus control group, SH group versus control group, and SH group versus negative control group. Functional enrichment analyses, protein–protein interaction network, and modules analyses were conducted. Target genes of hsa-miR-21-5p and transcription factors were predicted, followed by the regulatory network construction. Results: Minichromosome maintenance 10 replication initiation factor and cell division cycle associated 8 were important nodes in protein–protein interaction network with higher degrees. Cell division cycle associated 8 was enriched in cell division biological process. Furthermore, maintenance 10 replication initiation factor and cell division cycle associated 8 were significantly enriched in cluster 1 and micro-RNA-transcription factor-target genes regulating network. In addition, transcription factor Dp family member 3 (transcription factor of maintenance 10 replication initiation factor and cell division cycle associated 8) and RAD21 cohesin complex component (transcription factor of maintenance 10 replication initiation factor) were target genes of hsa-miR-21-5p. Conclusions: Micro-RNA-21 may play a key role in lung cancer partly via maintenance 10 replication initiation factor and cell division cycle associated 8. Furthermore, microRNA-21 targeted cell division cycle associated 8 and then played roles in lung cancer via the process of cell division. Transcription factor Dp family member 3 and RAD21 cohesin complex component are important transcription factors in microRNA-21-interfered lung cancer.

scholarly journals Functional properties ensue from cooperation of different interactions

2014 ◽  
Vol 70 (a1) ◽  
pp. C630-C630
Author(s):  
Giuseppe Resnati ◽  
Pierangelo Metrangolo ◽  
Giancarlo Terraneo ◽  
Gabriella Cavallo
Keyword(s):  
Hydrogen Bond ◽  
Self Assembly ◽  
Halogen Atom ◽  
Crystal Packing ◽  
Halogen Bond ◽  
Decisive Role ◽  
Solid Materials ◽  
Two Component ◽  
Confined Environment ◽  
Specific Profile

According to the definition recommended by IUPAC [1], a halogen bond (XB) occurs when there is evidence of a net attractive interaction between an electrophilic region in a halogen atom and a nucleophilic region in another atom. The halogen bond has many similarities with the hydrogen bond (HB) and here we discuss the specific profile of the two interactions. We also show how the cooperation between the two interactions afford crystalline systems possessing unique and useful properties. For instance, the diiodide, dibromide, and dichloride salts of the 1,6-bis(trimethylammonium)hexane cation (hexamethonium, HMET2+, cation) react with two equivalents of diiodine in a solid-gas reaction and the corresponding bis-trihalides (halogen bonded adducts) are formed [2]. No cavities are present in the starting dihalides and the observed behavior reveals the dynamically porous character of bis(trimethylammonium)alkane dihalides. In the obtained bis-trihalides a net of X-···H-C HBs (X=Cl, Br, I) plays a decisive role in controlling the crystal packing: Four cationic columns embrace an anionic twin column formed by stacking of trihalide dimers. When heated, these bis-trihalides lose one diiodine molecule and the virtually unknown tetrahalide dianions [I4]2-, [I2Br2] 2-, and [I2Cl2]2-are formed. These dianions are the product of the double pinning of a diiodine molecule by two halide anions via strong XBs. The last two tetrahalides were never obtained in solution. The confined environment of dynamically porous materials clearly confers useful synthetic opportunities relative to solution-state processes. Other cases are described wherein XB and HB cooperate in driving self-assembly processes which afford solid materials endowed with useful properties. For instance, we will discuss the formation of two-component supramolecular gels [3] wherein a bis-urea and a diiodoarene self-assemble via cooperative XB and HB.

Study on the mitochondrial apoptosis pathways of small cell lung cancer H446 cells induced by Trichinella spiralis muscle larvae ESPs

Parasitology ◽  
2017 ◽  
Vol 144 (6) ◽  
pp. 793-800 ◽  
Author(s):  
JINGMEI LUO ◽  
LI YU ◽  
GUANGCHENG XIE ◽  
DAN LI ◽  
MENG SU ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Trichinella Spiralis ◽  
Negative Control ◽  
Small Cell ◽  
Control Group ◽  
Secretory Proteins ◽  
Small Cell Lung ◽  
Antineoplastic Action

SUMMARYTrichinella spiralis (T.spiralis) muscle-larva (ML) excretory–secretory proteins (ESPs) contain antitumour-active substances. ESPs have been shown to inhibit tumour growth. To explore the effects of these proteins on small cell lung cancer cells and the possible mechanisms of their antineoplastic action, H446 SCLC cells were co-cultured with different concentrations of T. spiralis ML ESPs for 12, 24 and 48 h. Our results showed that T. spiralis ML ESPs significantly inhibited H446 cell proliferation, which was dose-and time-dependent. The results of flow cytometry testing indicate a clear apoptosis trend in H446 cells co-cultured with ESPs for 24 h. Reverse transcription polymerase chain reaction and Western blotting results showed increased expression of pro-apoptosis genes Bax, Cyt-C, Apaf-1, caspase-9 and caspase-3, compared with the negative control group, and decreased the expression of anti-apoptosis genes Bcl-2 and Livin. Our results suggest that T. spiralis ML ESPs can induce apoptosis in H446 cells through a mitochondrial pathway, which may be a mechanism of antineoplastic action in T. spiralis ML ESPs.

scholarly journals Inflammation during Lung Cancer Progression and Ethyl Pyruvate Treatment Observed by Pulmonary Functional Hyperpolarized 129Xe MRI in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Atsuomi Kimura ◽  
Seiya Utsumi ◽  
Akihiro Shimokawa ◽  
Renya Nishimori ◽  
Neil J. Stewart ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Gas Exchange ◽  
Cancer Progression ◽  
Ethyl Pyruvate ◽  
Late Phase ◽  
Precancerous Lesion ◽  
Lung Ventilation ◽  
Negative Control ◽  
Functional Changes ◽  
Hyperpolarized 129Xe

This study aimed to assess the suitability of hyperpolarized 129Xe (HPXe) MRI for noninvasive longitudinal evaluation of pulmonary function in preclinical lung cancer models. A mouse model of lung cancer (LC) was induced in 5 mice by intraperitoneal injection of urethane, while a negative-control (NC) mice (N = 5) was prepared by injection of saline solution. Longitudinal HPXe MRI was performed over a 5-month period to monitor lung ventilation and gas exchange. The treatment efficacy of ethyl pyruvate (EP), an anti-inflammatory drug, to the mouse LC model was monitored using HPXe MRI by commencing administration of EP pre (early-phase) and 1-month post (late-phase) injection of urethane (N = 5 mice for each group). Gas-exchange function in LC mice was significantly reduced at 1-month after urethane injection compared with NC mice administered with saline ( P < 0.01 ). Thereafter, it remained consistently lower than that of the NC group for the full 5-month measurement period. In contrast, the ventilation function of the LC model mice was not significantly different to that of the NC mice. Histological analysis revealed alveolar epithelial hyperplasia in LC mice alveoli at 1 month after urethane injection, and adenoma was confirmed 3 months after the injection. The early- and late-phase EP interventions were found to improve HPXe MRI metrics (reduced at 1 month postinjection of urethane) and significantly inhibit tumor growth. These results suggest that HPXe MRI gas-exchange metrics can be used to quantitatively assess changes in the precancerous lesion microenvironment and to evaluate therapeutic efficacy in cancer. Thus, HPXe MRI can be utilized to noninvasively monitor pulmonary pathology during LC progression and can visualize functional changes during therapy.

scholarly journals Prostasin regulates PD-L1 expression in human lung cancer cells

2021 ◽  
Vol 41 (7) ◽  
Author(s):  
Li-Mei Chen ◽  
Julius C. Chai ◽  
Bin Liu ◽  
Tara M. Strutt ◽  
K. Kai McKinstry ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Cancer Cells ◽  
Human Lung ◽  
Negative Regulator ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells ◽  
Epidermal Growth

Abstract The serine protease prostasin is a negative regulator of lipopolysaccharide-induced inflammation and has a role in the regulation of cellular immunity. Prostasin expression in cancer cells inhibits migration and metastasis, and reduces epithelial–mesenchymal transition. Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune response and its expression in cancer cells interferes with immune surveillance. The aim of the present study was to investigate if prostasin regulates PD-L1 expression. We established sublines overexpressing various forms of prostasin as well as a subline deficient for the prostasin gene from the Calu-3 human lung cancer cells. We report here that PD-L1 expression induced by interferon-γ (IFNγ) is further enhanced in cells overexpressing the wildtype membrane-anchored prostasin. The PD-L1 protein was localized on the cell surface and released into the culture medium in extracellular vesicles (EVs) with the protease-active prostasin. The epidermal growth factor-epidermal growth factor receptor (EGF-EGFR), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) participated in the prostasin-mediated up-regulation of PD-L1 expression. A Gene Set Enrichment Analysis (GSEA) of patient lung tumors in The Cancer Genome Atlas (TCGA) database revealed that prostasin and PD-L1 regulate common signaling pathways during tumorigenesis and tumor progression.

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