scholarly journals Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis

2022 ◽  
Author(s):  
Lukas P Feilen ◽  
Shu-Yu Chen ◽  
Akio Fukumori ◽  
Regina Feederle ◽  
Martin Zacharias ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Active Site ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Intramembrane Proteolysis ◽  
Structural Stabilization ◽  
Substrate Complex ◽  
Catalytic Active Site ◽  
Lipid Environment ◽  
Dynamics Simulations

Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimer's disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular dynamics simulations revealed that important elements for substrate binding such as transmembrane domain 6a of PSH are more labile in micelles and stabilized in the lipid bilayer. Moreover, consistent with an enhanced interaction of PSH with a transition-state analog inhibitor, the bilayer promoted the formation of the enzyme's catalytic active site geometry. Our data indicate that the lipid environment of an intramembrane protease plays a critical role in structural stabilization and active site arrangement of the enzyme-substrate complex thereby promoting intramembrane proteolysis.

scholarly journals Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms

2020 ◽  
Author(s):  
Anna Pabis ◽  
Robert J. Rawle ◽  
Peter M. Kasson
Keyword(s):  
Viral Entry ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Cellular Membrane ◽  
Membrane Curvature ◽  
Viral Envelope ◽  
Enveloped Viruses ◽  
Influenza Hemagglutinin ◽  
Hemagglutinin Protein ◽  
Dynamics Simulations

AbstractEnveloped viruses enter cells via a process of membrane fusion between the viral envelope and a cellular membrane. For influenza virus, mutational data have shown that the membrane-inserted portions of the hemagglutinin protein play a critical role in achieving fusion. In contrast to the relatively well-understood ectodomain, a predictive mechanistic understanding of the intramembrane mechanisms by which influenza hemagglutinin drives fusion has been elusive. We have used molecular dynamics simulations of fusion between a full-length hemagglutinin proteoliposome and a lipid bilayer to analyze these mechanisms. In our simulations, hemagglutinin first acts within the membrane to increase lipid tail protrusion and promote stalk formation and then acts to engage the distal leaflets of each membrane and promote stalk widening, curvature, and eventual fusion. These two sequential mechanisms, one occurring prior to stalk formation and one after, are consistent with experimental measurements we report of single-virus fusion kinetics to liposomes of different sizes. The resulting model also helps explain and integrate prior mutational and biophysical data, particularly the mutational sensitivity of the fusion peptide N-terminus and the length sensitivity of the transmembrane domain. We hypothesize that entry by other enveloped viruses may also utilize sequential processes of acyl tail exposure followed by membrane curvature and distal leaflet engagement.

scholarly journals Computational Characterizations of the Interactions Between the Pontacyl Violet 6R and Exoribonuclease as a Potential Drug Target Against SARS-CoV-2

2021 ◽  
Vol 8 ◽  
Author(s):  
Rangika Munaweera ◽  
Ying S. Hu
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Drug Target ◽  
Hydrophobic Interactions ◽  
Antiviral Treatment ◽  
Strong Interactions ◽  
Catalytic Active Site ◽  
The Stability ◽  
Dynamics Simulations ◽  
Novel Drug

We report a molecular-docking and virtual-screening-based identification and characterization of interactions of lead molecules with exoribonuclease (ExoN) enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From previously identified DEDDh/DEEDh subfamily nuclease inhibitors, our results revealed strong binding of pontacyl violet 6R (PV6R) at the catalytic active site of ExoN. The binding was found to be stabilized via two hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations further confirmed the stability of PV6R at the active site showing a shift in ligand to reach a more stabilized binding. Using PV6R as the lead molecule, we employed virtual screening to identify potential molecular candidates that form strong interactions at the ExoN active site. Our study paves ways for evaluating the ExoN as a novel drug target for antiviral treatment against SARS-CoV-2.

scholarly journals Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms

2020 ◽  
Vol 117 (13) ◽  
pp. 7200-7207 ◽  
Author(s):  
Anna Pabis ◽  
Robert J. Rawle ◽  
Peter M. Kasson
Keyword(s):  
Viral Entry ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Cellular Membrane ◽  
Membrane Curvature ◽  
Viral Envelope ◽  
Enveloped Viruses ◽  
Influenza Hemagglutinin ◽  
Hemagglutinin Protein ◽  
Dynamics Simulations

Enveloped viruses enter cells via a process of membrane fusion between the viral envelope and a cellular membrane. For influenza virus, mutational data have shown that the membrane-inserted portions of the hemagglutinin protein play a critical role in achieving fusion. In contrast to the relatively well-understood ectodomain, a predictive mechanistic understanding of the intramembrane mechanisms by which influenza hemagglutinin drives fusion has been elusive. We used molecular dynamics simulations of fusion between a full-length hemagglutinin proteoliposome and a lipid bilayer to analyze these mechanisms. In our simulations, hemagglutinin first acts within the membrane to increase lipid tail protrusion and promote stalk formation and then acts to engage the distal leaflets of each membrane and promote stalk widening, curvature, and eventual fusion. These two sequential mechanisms, one occurring before stalk formation and one after, are consistent with our experimental measurements of single-virus fusion kinetics to liposomes of different sizes. The resulting model also helps explain and integrate previous mutational and biophysical data, particularly the mutational sensitivity of the fusion peptide N terminus and the length sensitivity of the transmembrane domain. We hypothesize that entry by other enveloped viruses may also use sequential processes of acyl tail exposure, followed by membrane curvature and distal leaflet engagement.

Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study

2020 ◽  
Vol 22 (9) ◽  
pp. 635-648 ◽  
Author(s):  
Korosh Mashayekh ◽  
Shahrzad Sharifi ◽  
Tahereh Damghani ◽  
Maryam Elyasi ◽  
Mohammad S. Avestan ◽  
...  
Keyword(s):  
Critical Role ◽  
Scientific Work ◽  
Binding Mode ◽  
Docking Studies ◽  
Conformational Space ◽  
Hydrogen Bond Interactions ◽  
Docking Program ◽  
Dynamics Simulations ◽  
Computational Drug Discovery ◽  
Dynamic Ensembles

Background: c-Met kinase plays a critical role in a myriad of human cancers, and a massive scientific work was devoted to design more potent inhibitors. Objective: In this study, 16 molecular dynamics simulations of different complexes of potent c-Met inhibitors with U-shaped binding mode were carried out regarding the dynamic ensembles to design novel potent inhibitors. Methods: A cluster analysis was performed, and the most representative frame of each complex was subjected to the structure-based pharmacophore screening. The GOLD docking program investigated the interaction energy and pattern of output hits from the virtual screening. The most promising hits with the highest scoring values that showed critical interactions with c-Met were presented for ADME/Tox analysis. Results: The screening yielded 45,324 hits that all of them were subjected to the docking studies and 10 of them with the highest-scoring values having diverse structures were presented for ADME/Tox analyses. Conclusion: The results indicated that all the hits shared critical Pi-Pi stacked and hydrogen bond interactions with Tyr1230 and Met1160 respectively.

scholarly journals Crystal Structure of Escherichia coli Agmatinase: Catalytic Mechanism and Residues Relevant for Substrate Specificity

2021 ◽  
Vol 22 (9) ◽  
pp. 4769
Author(s):  
Pablo Maturana ◽  
María S. Orellana ◽  
Sixto M. Herrera ◽  
Ignacio Martínez ◽  
Maximiliano Figueroa ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Conformational Dynamics ◽  
High Specificity ◽  
Arginine Decarboxylase ◽  
Space Groups ◽  
X Ray Crystallography ◽  
High Dynamics ◽  
Dynamics Simulations

Agmatine is the product of the decarboxylation of L-arginine by the enzyme arginine decarboxylase. This amine has been attributed to neurotransmitter functions, anticonvulsant, anti-neurotoxic, and antidepressant in mammals and is a potential therapeutic agent for diseases such as Alzheimer’s, Parkinson’s, and cancer. Agmatinase enzyme hydrolyze agmatine into urea and putrescine, which belong to one of the pathways producing polyamines, essential for cell proliferation. Agmatinase from Escherichia coli (EcAGM) has been widely studied and kinetically characterized, described as highly specific for agmatine. In this study, we analyze the amino acids involved in the high specificity of EcAGM, performing a series of mutations in two loops critical to the active-site entrance. Two structures in different space groups were solved by X-ray crystallography, one at low resolution (3.2 Å), including a guanidine group; and other at high resolution (1.8 Å) which presents urea and agmatine in the active site. These structures made it possible to understand the interface interactions between subunits that allow the hexameric state and postulate a catalytic mechanism according to the Mn2+ and urea/guanidine binding site. Molecular dynamics simulations evaluated the conformational dynamics of EcAGM and residues participating in non-binding interactions. Simulations showed the high dynamics of loops of the active site entrance and evidenced the relevance of Trp68, located in the adjacent subunit, to stabilize the amino group of agmatine by cation-pi interaction. These results allow to have a structural view of the best-kinetic characterized agmatinase in literature up to now.

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