Ebru Demet Akdoğan

Akdoğan, Ebru Demet

Name Variants

Akdoğan, E.
Akdoğan, EBRU DEMET
E. D. Akdoğan
A., Ebru Demet
Ebru Demet Akdoğan
Akten E.
Akdoğan,E.D.
AKDOĞAN, EBRU DEMET
Akdogan,Ebru Demet
Akdogan,E.D.
Akdogan, Ebru Demet
Ebru Demet AKDOĞAN
E. Akdoğan
EBRU DEMET AKDOĞAN
Ebru Demet, Akdogan
Akdoğan, Ebru Demet
Akdoğan, E. D.
A.,Ebru Demet
AKDOĞAN, Ebru Demet
Demet Akdoğan, Ebru
Akten, Ebru Demet
Akdoğan, Ebru Demet
Akdoğan, Ebru Demet
Akdoğan, Demet Akten

Job Title

Prof. Dr.

Email Address

demet.akten@khas.edu.tr

Main Affiliation

Molecular Biology and Genetics

Scholarly Output

38

Articles

22

Citation Count

41

Supervised Theses

7 Scholarly Output Search Results

Now showing 1 - 9 of 9

Citation - WoS: 1
Citation - Scopus: 1
Tunnel-Like Region Observed as a Potential Allosteric Site In Staphylococcus Aureus Glyceraldehyde-3 Dehydrogenase
(Elsevier Science inc, 2024) Guner-Yilmaz, Ozde Zeynep; Akdoğan, Ebru Demet; Kurkcuoglu, Ozge; Akten, Ebru Demet
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzing the sixth step of glycolysis has been investigated for allosteric features that might be used as potential target for specific inhibition of Staphylococcus aureus (S.aureus). X-ray structure of bacterial enzyme for which a tunnel-like opening passing through the center previously proposed as an allosteric site has been subjected to six independent 500 ns long Molecular Dynamics simulations. Harmonic bond restraints were employed at key residues to underline the allosteric feature of this region. A noticeable reduction was observed in the mobility of NAD+ binding domains when restrictions were applied. Also, a substantial decrease in cross-correlations between distant C alpha fluctuations was detected throughout the structure. Mutual information (MI) analysis revealed a similar decrease in the degree of correspondence in positional fluctuations in all directions everywhere in the receptor. MI between backbone and sidechain torsional variations changed its distribution profile and decreased considerably around the catalytic sites when restraints were employed. Principal component analysis clearly showed that the restrained state sampled a narrower range of conformations than apo state, especially in the first principal mode due to restriction in the conformational flexibility of NAD+ binding domain. Clustering the trajectory based on catalytic site residues displayed a smaller repertoire of conformations for restrained state compared to apo. Representative snapshots subjected to k-shortest pathway analysis revealed the impact of bond restraints on the allosteric communication which displayed distinct optimal and suboptimal pathways for two states, where observed frequencies of critical residues Gln51 and Val283 at the proposed site changed considerably.
Citation - WoS: 18
Citation - Scopus: 20
Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets
(Frontiers Media, 2020) Ayyıldız, Merve; Akdoğan, Ebru Demet; Çeliker, Serkan; Özhelvacı, Fatih; Akten, Ebru Demet
Three allosteric glycolytic enzymes, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase and pyruvate kinase, associated with bacterial, parasitic and human species, were explored to identify potential allosteric sites that would be used as prime targets for species-specific drug design purposes using a newly developed approach which incorporates solvent mapping, elastic network modeling, sequence and structural alignments. The majority of binding sites detected by solvent mapping overlapped with the interface regions connecting the subunits, thus appeared as promising target sites for allosteric regulation. Each binding site was then evaluated by its ability to alter the global dynamics of the receptor defined by the percentage change in the frequencies of the lowest-frequency modes most significantly and as anticipated, the most effective ones were detected in the vicinity of the well-reported catalytic and allosteric sites. Furthermore, some of our proposed regions intersected with experimentally resolved sites which are known to be critical for activity regulation, which further validated our approach. Despite the high degree of structural conservation encountered between bacterial/parasitic and human glycolytic enzymes, the majority of the newly presented allosteric sites exhibited a low degree of sequence conservation which further increased their likelihood to be used as species-specific target regions for drug design studies.
Investigation of Species-Specific Allosteric Binding Sites in Glycolytic Enzymes Via Allosigma and Molecular Dynamics Simulations
(Kadir Has Üniversitesi, 2021) Çelebi, Metehan; Akdoğan, Ebru Demet; Demet Akdoğan, Ebru
In previous studies of our research group, allosteric sites have been proposed to be used as drug targets in species-specific drug design studies for phosphofructokinase (PFK), glyceraldehyde-3 phosphate dehydrogenase (GADPH) and pyruvate kinase (PK) that belong to three species bacteria, parasite, and human and are essential enzymes in the glycolytic pathway. In this thesis, they were further investigated by various tools such as AlloSigMA and MD simulations. In addition to proposed allosteric sites, known allosteric sites reported by experimental studies for S. aureus PFK and PK enzymes were also investigated. In the first part, AlloSigMA was used to perturb the residues at the proposed and/or known allosteric sites in order to evaluate their allosteric capacities and their effects on protein dynamics. Accordingly, a reduced dynamics in the catalytic sites indicating allosteric inhibition was observed for most of the proposed allosteric sites whereas either an opposite or no effect was observed for known allosteric sites. In addition, partial allosteric inhibition was observed for some of the proposed allosteric sites in human species. In the second part of this thesis, Molecular Dynamics simulations of a total of nine runs, each 100 ns long, were performed for S. aureus phosphofructokinase enzyme in apo and constrained states which incorporated bond restraints at the proposed and known allosteric sites. Here, the goal was to investigate the effect of restraints on the protein's global dynamics. RMSD/RMSF, principal component analysis, the change in orthogonal principal axes, and the mean square distance fluctuation between each pair of residues were determined. According to PCA analysis, increase in the correlation of positional fluctuations between each pair of residues in the chains and domains were observed. Based on the mean square distance fluctuation between residue pairs, each dimer started to communicate more within itself when switched to constrained state.
Investigation Of Allosteric İnhibition Effect İn Pyruvate Kinase By Constrained Molecular Dynamics Simulation Method Piruvat Kinazın Allosterik Olarak İnhibe Edilmesinin Kısıtlanmış Moleküler Dinamik Similasyon Methodu Kullanılarak İncelenmesi
(Kadir Has Üniversitesi, 2021) Akkaya, Reyhan; Akdoğan, Ebru Demet; Akdoğan, Ebru Demet
In previous studies, our research group identified species-specific allosteric sites in glycolytic enzymes from different organisms and identified candidate inhibitory molecules that strongly interact with the residues at these sites. In this study, a Molecular Dynamics simulation study was performed on one of the glycolytic enzymes, bacterial pyruvate kinase (S. aureus PK), by employing bond restraints between selected pairs of residues at the suggested allosteric region in order to mimic the presence of a drug molecule. At the same time, interacting residues in an ex- perimentally identified allosteric region were also restricted and compared with the proposed area. Three 100 ns long independent runs were conducted for each of three different states of the receptor; apo state (no restraints), constr-1 (restriction on proposed allosteric site) and constr-2 (restriction on known allosteric site) which amount to a total of nine runs, e.g., 900 ns. Several analytical methods were used to elucidate the effect of restricted regions on protein dynamics and the allosteric character of pyruvate kinase. While structural changes were examined with RMSD-RMSF analysis, correlations between global movements and structural components were analysed with principal component analysis. From PCA results, it was observed that both restricted allosteric regions led to decreased correlations of positional fluctuations in comparison to apo state. Investigation of changes in the secondary structure at the catalytic site showed that the α′6 helix, which has an essential role in the stabilization of the active structure, shifted to a coil-turn structure in the apo state more frequently than in the con- strained states. Additionally, domain rotations identified via principal axes analysis, showed that the constrained state disrupted the domain rotations more often. Finally, the distance fluctuation analysis was performed to observe the effect of the restricted residues in the allosteric signal transduction. The communications be- tween residues increased in the constr-1 state while there was slight decrease in the communications of the constr-2 state.
Citation - WoS: 2
Citation - Scopus: 2
Altered Dynamics of S. Aureus Phosphofructokinase Via Bond Restraints at Two Distinct Allosteric Binding Sites
(Academic Press Ltd- Elsevier Science Ltd, 2022) Celebi, Metehan; Akdoğan, Ebru Demet; Akten, Ebru Demet
The effect of perturbation at the allosteric site was investigated through several replicas of molecular dynamics (MD) simulations conducted on bacterial phosphofructokinase (SaPFK). In our previous work, an alternative binding site was estimated to be allosteric in addition to the experimentally reported one. To highlight the effect of both allosteric sites on receptor's dynamics, MD runs were carried out on apo forms with and without perturbation. Perturbation was achieved via incorporating multiple bond restraints for residue pairs located at the allosteric site. Restraints applied to the predicted site caused one dimer to stiffen, whereas an increase in mobility was detected in the same dimer when the experimentally resolved site was restrained. Fluctuations in C-alpha-C-alpha distances which is used to disclose residues with high potential of communication indicated a marked increase in signal transmission within each dimer as the receptor switched to a restrained state. Cross-correlation of positional fluctuations indicated an overall decrease in the magnitude of both positive and negative correlations when restraints were employed on the predicted allosteric site whereas an exact opposite effect was observed for the reported site. Finally, mutual correspondence between positional fluctuations noticeably increased with restraints on predicted allosteric site, whereas an opposite effect was observed for restraints applied on experimentally reported one. In view of these findings, it is clear that the perturbation of either one of two allosteric sites effected the dynamics of the receptor with a distinct and contrasting character. (c) 2022 Elsevier Ltd. All rights reserved.
Citation - WoS: 2
Citation - Scopus: 2
Information Transfer in Active States of Human ?2-Adrenergic Receptor Via Inter-Rotameric Motions of Loop Regions
(Mdpi, 2022) Sogunmez, Nuray; Akdoğan, Ebru Demet; Akten, Ebru Demet
Featured Application Loop regions in beta(2)AR are critical hot spot regions, likely in other GPCRs, and can be used as potential allosteric drug targets. Two independent 1.5 mu s long MD simulations were conducted for the fully atomistic model of the human beta2-adrenergic receptor (beta(2)AR) in a complex with a G protein to investigate the signal transmission in a fully active state via mutual information and transfer entropy based on alpha-carbon displacements and rotameric states of backbone and side-chain torsion angles. Significant correlations between fluctuations in alpha-Carbon displacements were mostly detected between transmembrane (TM) helices, especially TM5 and TM6 located at each end of ICL3 and TM7. Signal transmission across beta(2)-AR was quantified by shared mutual information; a high amount of correspondence was distinguished in almost all loop regions when rotameric states were employed. Moreover, polar residues, especially Arg, made the most contribution to signal transmission via correlated side-chain rotameric fluctuations as they were more frequently observed in loop regions than hydrophobic residues. Furthermore, transfer entropy identified all loop regions as major entropy donor sites, which drove future rotameric states of torsion angles of residues in transmembrane helices. Polar residues appeared as donor sites from which entropy flowed towards hydrophobic residues. Overall, loops in beta(2)AR were recognized as potential allosteric hot spot regions, which play an essential role in signal transmission and should likely be used as potential drug targets.
Citation - WoS: 7
Citation - Scopus: 7
Potential allosteric sites captured in glycolytic enzymes via residue-based network models: Phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase
(Elsevier, 2022) Akdoğan, Ebru Demet; Inan, Tugce; Kurkcuoglu, Ozge; Akten, Ebru Demet
Likelihood of new allosteric sites for glycolytic enzymes, phosphofructokinase (PFK), glyceraldehyde-3phosphate dehydrogenase (GADPH) and pyruvate kinase (PK) was evaluated for bacterial, parasitic and human species. Allosteric effect of a ligand binding at a site was revealed on the basis of low-frequency normal modes via C alpha-harmonic residue network model. In bacterial PFK, perturbation of the proposed allosteric site outperformed the known allosteric one, producing a high amount of stabilization or reduced dynamics, on all catalytic regions. Another proposed allosteric spot at the dimer interface in parasitic PFK exhibited major stabilization effect on catalytic regions. In parasitic GADPH, the most desired allosteric response was observed upon perturbation of its tunnel region which incorporated key residues for functional regulation. Proposed allosteric site in bacterial PK produced a satisfactory allosteric response on all catalytic regions, whereas in human and parasitic PKs, a partial inhibition was observed. Residue network model based solely on contact topology identified the 'hub residues' with high betweenness tracing plausible allosteric communication pathways between distant functional sites. For both bacterial PFK and PK, proposed sites accommodated hub residues twice as much as the known allosteric site. Tunnel region in parasitic GADPH with the strongest allosteric effect among species, incorporated the highest number of hub residues. These results clearly suggest a one-to-one correspondence between the degree of allosteric effect and the number of hub residues in that perturbation site, which increases the likelihood of its allosteric nature.
Citation - WoS: 2
Citation - Scopus: 2
Drug Repositioning To Propose Alternative Modulators for Glucocorticoid Receptor Through Structure-Based Virtual Screening
(Taylor & Francis Inc, 2022) Metin, Reyhan; Akdoğan, Ebru Demet; Akten, Ebru Demet
Drug repositioning has recently become one of the widely used drug design approaches in proposing alternative compounds with potentially fewer side effects. In this study, structure-based pharmacophore modelling and docking was used to screen existing drug molecules to bring forward potential modulators for ligand-binding domain of human glucocorticoid receptor (hGR). There exist several drug molecules targeting hGR, yet their apparent side effects still persist. Our goal was to disclose new compounds via screening existing drug compounds to bring forward fast and explicit solutions. The so-called shared pharmacophore model was created using the most persistent pharmacophore features shared by several crystal structures of the receptor. The shared model was first used to screen a small database of 75 agonists and 300 antagonists/decoys, and exhibited a successful outcome in its ability to distinguish agonists from antagonists/decoys. Then, it was used to screen a database of over 5000 molecules composed of FDA-approved, worldwide used and investigational drug compounds. A total of 110 compounds satisfying the pharmacophore requirements were subjected to different docking experiments for further assessment of their binding ability. In the final hit list of 54 compounds which fulfilled all scoring criteria, 19 of them were nonsteroidal and when further investigated, each presented a unique scaffold with little structural resemblance to any known nonsteroidal GR modulators. Independent 100 ns long MD simulations conducted on three selected drug candidates in complex with hGR displayed stable conformations incorporating several hydrogen bonds common to all three compounds and the reference molecule dexamethasone.
Citation - WoS: 6
Citation - Scopus: 7
Distinctive Communication Networks in Inactive States of Beta(2)-Adrenergic Receptor: Mutual Information and Entropy Transfer Analysis
(Wiley, 2020) Soğünmez, Nuray; Söğünmez Erdoğan, Nuray; Akten, Ebru Demet; Akdoğan, Ebru Demet
Mutual information and entropy transfer analysis employed on two inactive states of human beta-2 adrenergic receptor (beta(2)-AR) unraveled distinct communication pathways. Previously, a so-called "highly" inactive state of the receptor was observed during 1.5 microsecond long molecular dynamics simulation where the largest intracellular loop (ICL3) was swiftly packed onto the G-protein binding cavity, becoming entirely inaccessible. Mutual information quantifying the degree of correspondence between backbone-C(alpha)fluctuations was mostly shared between intra- and extra-cellular loop regions in the original inactive state, but shifted to entirely different regions in this latest inactive state. Interestingly, the largest amount of mutual information was always shared among the mobile regions. Irrespective of the conformational state, polar residues always contributed more to mutual information than hydrophobic residues, and also the number of polar-polar residue pairs shared the highest degree of mutual information compared to those incorporating hydrophobic residues. Entropy transfer, quantifying the correspondence between backbone-C(alpha)fluctuations at different timesteps, revealed a distinctive pathway directed from the extracellular site toward intracellular portions in this recently exposed inactive state for which the direction of information flow was the reverse of that observed in the original inactive state where the mobile ICL3 and its intracellular surroundings drove the future fluctuations of extracellular regions.