How an Inhibitor Bound To Subunit Interface Alters Triosephosphate Isomerase Dynamics

dc.contributor.author Kürkçüoğlu, Zeynep
dc.contributor.author Akdoğan, Ebru Demet
dc.contributor.author Fındık, Doğa
dc.contributor.author Akdoğan, Ebru Demet
dc.contributor.author Doruker, Pemra
dc.contributor.other Molecular Biology and Genetics
dc.date.accessioned 2019-06-27T08:02:13Z
dc.date.available 2019-06-27T08:02:13Z
dc.date.issued 2015
dc.department Fakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümü en_US
dc.description.abstract The tunnel region at triosephosphate isomerase (TIM)'s dimer interface distant from its catalytic site is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor named bt10. Within the time frame of our MD simulations we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10 which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54000 MD snapshots. Using this computationally efficient technique we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly we observed allosteric changes in the catalytic loop's dynamics flexibility and correlations as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme. en_US]
dc.identifier.citationcount 24
dc.identifier.doi 10.1016/j.bpj.2015.06.031 en_US
dc.identifier.endpage 1178
dc.identifier.issn 0006-3495 en_US
dc.identifier.issn 1542-0086 en_US
dc.identifier.issn 0006-3495
dc.identifier.issn 1542-0086
dc.identifier.issue 6
dc.identifier.pmid 26190635 en_US
dc.identifier.scopus 2-s2.0-84941807856 en_US
dc.identifier.scopusquality Q1
dc.identifier.startpage 1169 en_US
dc.identifier.uri https://hdl.handle.net/20.500.12469/573
dc.identifier.uri https://doi.org/10.1016/j.bpj.2015.06.031
dc.identifier.volume 109 en_US
dc.identifier.wos WOS:000361565400013 en_US
dc.identifier.wosquality Q2
dc.institutionauthor Akdoğan, Ebru Demet en_US
dc.language.iso en en_US
dc.publisher Cell Press en_US
dc.relation.journal Biophysical Journal en_US
dc.relation.publicationcategory Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı en_US
dc.rights info:eu-repo/semantics/openAccess en_US
dc.scopus.citedbyCount 25
dc.title How an Inhibitor Bound To Subunit Interface Alters Triosephosphate Isomerase Dynamics en_US
dc.type Article en_US
dc.wos.citedbyCount 24
dspace.entity.type Publication
relation.isAuthorOfPublication 558d2b8e-c713-49e0-9350-d354abb5cd69
relation.isAuthorOfPublication.latestForDiscovery 558d2b8e-c713-49e0-9350-d354abb5cd69
relation.isOrgUnitOfPublication 71ce8622-7449-4a6a-8fad-44d881416546
relation.isOrgUnitOfPublication.latestForDiscovery 71ce8622-7449-4a6a-8fad-44d881416546

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
How an Inhibitor Bound to Subunit Interface Alters Triosephosphate.pdf
Size:
1.92 MB
Format:
Adobe Portable Document Format
Description: