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The pursuit of new alternative ways to eradicate Helicobacter pylori continues: Detailed characterization of interactions in the adenylosuccinate synthetase active site

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cris.lastimport.scopus2024-02-12T19:55:20Z
dc.abstract.enPurine nucleotide synthesis is realised only through the salvage pathway in pathogenic bacterium Helicobacter pylori. Therefore, the enzymes of this pathway, among them also the adenylosuccinate synthetase (AdSS), present potential new drug targets. This paper describes characterization of His6-tagged AdSS from H. pylori. Thorough analysis of 3D-structures of fully ligated AdSS (in a complex with guanosine diphosphate, 6-phosphoryl-inosine monophosphate, hadacidin and Mg2+) and AdSS in a complex with inosine monophosphate (IMP) only, enabled identification of active site interactions crucial for ligand binding and enzyme activity. Combination of experimental and molecular dynamics (MD) simulations data, particularly emphasized the importance of hydrogen bond Arg135-IMP for enzyme dimerization and active site formation. The synergistic effect of substrates (IMP and guanosine triphosphate) binding was suggested by MD simulations. Several flexible elements of the structure (loops) are stabilized by the presence of IMP alone, however loops comprising residues 287–293 and 40–44 occupy different positions in two solved H. pylori AdSS structures. MD simulations discovered the hydrogen bond network that stabilizes the closed conformation of the residues 40–50 loop, only in the presence of IMP. Presented findings provide a solid basis for the design of new AdSS inhibitors as potential drugs against H. pylori.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorBzowska, Maria
dc.contributor.authorAšler, Ivana Leščić
dc.contributor.authorLuić, Marija
dc.contributor.authorŠtefanić, Zoran
dc.contributor.authorBertoša, Branimir
dc.contributor.authorPavkov-Keller, Tea
dc.contributor.authorWiniewska-Szajewska, Maria
dc.contributor.authorWielgus-Kutrowska, Beata
dc.contributor.authorMaksymiuk, Weronika
dc.contributor.authorWojtyś, Marta
dc.contributor.authorPetek, Ana
dc.contributor.authorNarczyk, Marta
dc.contributor.authorBubić, Ante
dc.date.accessioned2024-01-26T10:36:33Z
dc.date.available2024-01-26T10:36:33Z
dc.date.issued2023
dc.description.financePublikacja bezkosztowa
dc.description.volume226
dc.identifier.doi10.1016/J.IJBIOMAC.2022.12.001
dc.identifier.issn0141-8130
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/122922
dc.identifier.weblinkhttps://api.elsevier.com/content/article/PII:S0141813022028926?httpAccept=text/xml
dc.languageeng
dc.pbn.affiliationphysical sciences
dc.relation.ispartofInternational Journal of Biological Macromolecules
dc.relation.pages37-50
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleThe pursuit of new alternative ways to eradicate Helicobacter pylori continues: Detailed characterization of interactions in the adenylosuccinate synthetase active site
dc.typeJournalArticle
dspace.entity.typePublication