scholarly journals Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding

2019 ◽  
Vol 20 (24) ◽  
pp. 6256 ◽  
Author(s):  
Raju Dash ◽  
Md. Chayan Ali ◽  
Nayan Dash ◽  
Md. Abul Kalam Azad ◽  
S. M. Zahid Hosen ◽  
...  
Keyword(s):  
Binding Energy ◽  
Cancer Progression ◽  
Conformational Changes ◽  
Substrate Binding ◽  
Dynamics Simulation ◽  
Loss Of Function ◽  
Functional Consequences ◽  
Binding Energy Analysis ◽  
Exogenous Compounds

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235–263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.

scholarly journals Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Derek N. Lavery ◽  
Charlotte L. Bevan
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Histone Deacetylases ◽  
Transcriptional Response ◽  
Fine Tuning ◽  
Receptor Signalling ◽  
Prostate Carcinogenesis ◽  
Functional Consequences

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly mediates these effects by modulating gene expression. During transcriptional regulation, the AR recruits numerous cofactors with acetylation-modifying enzymatic activity, the best studied include p300/CBP and the p160/SRC family of coactivators. It is known that recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key in fine-tuning responses to androgens and is thus likely to play a role in prostate cancer progression. Further, these proteins can also modify the AR itself. The functional consequences of AR acetylation, the role of modifying enzymes in relation to AR transcriptional response, and prostate cancer will be discussed.

scholarly journals Mechanistic insights into the deleterious role of nasu-hakola disease associated TREM2 variants

2019 ◽  
Author(s):  
Raju Dash ◽  
Ho Jin Choi ◽  
Il Soo Moon
Keyword(s):  
Myeloid Cells ◽  
Structural Features ◽  
Dynamics Simulation ◽  
Loss Of Function ◽  
Wild Type ◽  
Structural Impact ◽  
Collective Motions ◽  
Loop Regions ◽  
Complementarity Determining Region

AbstractRecently, critical roles of genetic variants in Triggering Receptor Expressed on Myeloid cells 2 (TREM2) for myeloid cells to Alzhimer’s disease have been aggressively highlighted. However, little studies focused to the deleterious role of Nasu-Hakola disease (NHD) associated TREM2 variants. In order to get insights into the contributions of these variants in neurodegeneration, we investigated the influences of three well-known NHD associated TREM2 mutations (Y38C, T66M and V126G) on the loss-of-function by using conventional molecular dynamics simulation. Compared to the wild type, the mutants produced substantial differences in the collective motions in the loop regions, which not only promotes structural remodelling in complementarity-determining region 2 (CDR2) loop but also in CDR1 loop, through changing the inter and intra-loop hydrogen bonding network. In addition, the structural studies from free energy landscape showed that Y38, T66 and V126 are crucial for maintaining structural features of CDR1 and CDR2 loops, while their mutation at this position produced steric clash and thus contributes to the structural impact and loss of ligand binding. These results revealed that the presence of the mutations in TREM2 ectodomain induced flexibility and promotes structural alterations. Dynamical scenarios, which are provided by the present study, may be critical to our understanding of the role of the three TREM2 mutations in neurodegenerative diseases.

scholarly journals Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4589 ◽  
Author(s):  
Taj Mohammad ◽  
Sagar Batra ◽  
Rashmi Dahiya ◽  
Mohammad Hassan Baig ◽  
Irfan Ahmad Rather ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Conformational Changes ◽  
Interaction Analysis ◽  
Interaction Mechanism ◽  
Structural Similarity ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Cyclin Dependent Kinase ◽  
Pubchem Database ◽  
Cycle Regulation

Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-N,6-N-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation.

scholarly journals Evidence of a Prion-Like Transmission of p53 Amyloid in Saccharomyces cerevisiae

2017 ◽  
Vol 37 (18) ◽  
Author(s):  
Shinjinee Sengupta ◽  
Samir K. Maji ◽  
Santanu K. Ghosh
Keyword(s):  
Cancer Progression ◽  
Rational Design ◽  
P53 Protein ◽  
Cell Types ◽  
Mutant P53 ◽  
Loss Of Function ◽  
Multiple Cancer ◽  
Aggregation Inhibitors ◽  
Specific Peptide

ABSTRACT Loss of p53 function is largely responsible for the occurrence of cancer in humans. Aggregation of mutant p53 has been found in multiple cancer cell types, suggesting a role of aggregation in loss of p53 function and cancer development. The p53 protein has recently been hypothesized to possess a prion-like conformation, although experimental evidence is lacking. Here, we report that human p53 can be inactivated upon exposure to preformed fibrils containing an aggregation-prone sequence-specific peptide, PILTIITL, derived from p53, and the inactive state was found to be stable for many generations. Importantly, we provide evidence of a prion-like transmission of these p53 aggregates. This study has significant implications for understanding cancer progression due to p53 malfunctioning without any loss-of-function mutation or occurrence of transcriptional inactivation. Our data might unlock new possibilities for understanding the disease and will lead to rational design of p53 aggregation inhibitors for the development of drugs against cancer.

scholarly journals Role of the fourth transmembrane domain in proton-coupled folate transporter function as assessed by the substituted cysteine accessibility method

2013 ◽  
Vol 304 (12) ◽  
pp. C1159-C1167 ◽  
Author(s):  
Daniel Sanghoon Shin ◽  
Rongbao Zhao ◽  
Andras Fiser ◽  
I. David Goldman
Keyword(s):  
Transmembrane Domain ◽  
Substrate Binding ◽  
Basolateral Membrane ◽  
Homology Model ◽  
Binding Pocket ◽  
Ependymal Cells ◽  
Loss Of Function ◽  
Substituted Cysteine Accessibility ◽  
Proximal Small Intestine

The proton-coupled folate transporter (PCFT, SLC46A1) mediates folate transport across the apical brush-border membrane of the proximal small intestine and the basolateral membrane of choroid plexus ependymal cells. Two loss-of-function mutations in PCFT, which are the basis for hereditary folate malabsorption, have been identified within the fourth transmembrane domain (TMD4) in subjects with this disorder. We have employed the substituted Cys accessibility method (SCAM) to study the accessibilities of all residues in TMD4 and their roles in folate substrate binding to the carrier. When residues 146–167 were replaced by Cys, all except R148C were expressed at the cell surface. Modification of five of these substituted Cys residues (positions 147, 152, 157, 158, and 161) by methanethiosulfonate (MTS) reagents led to reduction of PCFT function. All five residues could be labeled with N-biotinylaminoethyl-MTS, and this could be blocked by the high-affinity PCFT substrate pemetrexed. Pemetrexed also protected PCFT mutant function from inhibitory modification of the substituted Cys at positions 157, 158, and 161 by a MTS. The findings indicate that these five residues in TMD4 are accessible to the aqueous translocation pathway, play a role in folate substrate binding, and are likely located within or near the folate binding pocket. A homology model of PCFT places three of these residues, Phe157, Gly158, and Leu161, within a breakpoint in the midportion of TMD4, a region that likely participates in alterations in the PCFT conformational state during carrier cycling.

scholarly journals Molecular Dynamics of SARS-CoV-2 Nsp1 Structural Changes Associated with Variant Mutations

2021 ◽  
Author(s):  
Shokouh Rezaei ◽  
Yahya Sefidbakht ◽  
Filipe Pereira
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Structural Changes ◽  
Structure And Function ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Wild Type ◽  
Deletion Mutations ◽  
And Function

Abstract SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interact with viral RNA. Despite the relevance of Nsp1, few studies have been conducted to understand the effect of mutations on Nsp1 structure and function. Here, we provide a molecular dynamics simulation of SARS-CoV-2 Nsp1, wild type and variants. We found that SARS-CoV-2 Nsp1 has a more Rg value than SARS-CoV-1 Nsp1, with indicate an effect on the folding protein. This result suggest that SARS-CoV-2 Nsp1 can more easily approach the active site of the ribosome compared to SARS-CoV-1 Nsp1. In addition, we found that the C-terminal of the SARS-CoV-2 Nsp1, in particular residues 164 to 170, are more flexible than other regions of SARS-CoV-2 Nsp1 and SARS-CoV-1 Nsp1, confirming the role of this region in the interaction with the 40S subunit. Moreover, multiple deletion mutations have been found in the N/C-terminal of the SARS-CoV-2 Nsp1, which seems the effect of SARS-CoV-2 Nsp1 multiple deletions is greater than that of substitutions. Among all deletions, D156-158 and D80-90 may destabilize the protein structure and possibly increase the virulence of the SARS-CoV-2. Overall, our findings reinforce the importance of studying Nsp1 conformational changes in new variants and its effect on virulence of SARS-CoV-2.

scholarly journals N6-Methyladenosine Modification of PTTG3P Contributes to Colorectal Cancer Proliferation via YAP1

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Zheng ◽  
Yue Wang ◽  
Yiyang Liu ◽  
Longfei Xie ◽  
Jinnian Ge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Expression Profiles ◽  
Critical Role ◽  
Methylation Status ◽  
Tumor Model ◽  
Loss Of Function ◽  
Cancer Proliferation ◽  
Mrna Binding

BackgroundLong noncoding RNAs (lncRNAs) have emerged to have irreplaceable roles in the epigenetic regulation of cancer progression, but their biological functions in colorectal cancer (CRC) remain unclear.MethodsLncRNA expression profiles in CRC tissue and their normal counterpart were explored. Through gain and loss of function approaches, the role of lncRNA PTTG3P was validated in relevant CRC cells and subcutaneous tumor model. The correlations of PTTG3P expression with clinical outcomes were assessed.ResultsPTTG3P was upregulated in CRC tissues and was closely correlated with unsatisfactory prognosis. PTTG3P facilitated glycolysis and proliferation, and the transcriptional regulator YAP1 was necessary for PTTG3P-induced proliferation. Mechanistically, the N6-methyladenosine (m6A) subunit METTL3 increased PTTG3P expression by influencing its stability, while insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) could identify PTTG3P m6A methylation status and bind to it. IGF2BP2 knockdown partly recovered PTTG3P expression induced by METTL3, indicating that METTL3-regulated PTTG3P expression depended on the presence of IGF2BP2. Finally, rescue assays validated the critical role of the METTL3/PTTG3P/YAP1 axis on CRC proliferation.ConclusionsPTTG3P is an independent prognostic biomarker for CRC. The METTL3/PTTG3P/YAP1 axis promotes the progression of CRC and is a promising treatment target.

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