دورية أكاديمية
أعرض في EDS

Human O -GlcNAcase Uses a Preactivated Boat-skew Substrate Conformation for Catalysis. Evidence from X-ray Crystallography and QM/MM Metadynamics.

التفاصيل البيبلوغرافية
العنوان: Human O -GlcNAcase Uses a Preactivated Boat-skew Substrate Conformation for Catalysis. Evidence from X-ray Crystallography and QM/MM Metadynamics.
المؤلفون: Calvelo M; Departament de Química Inorgànica i Orgànica & IQTCUB, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain., Males A; York Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5DD, United Kingdom., Alteen MG; Department of Chemistry & Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada., Willems LI; York Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5DD, United Kingdom., Vocadlo DJ; Department of Chemistry & Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada., Davies GJ; York Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York YO10 5DD, United Kingdom., Rovira C; Departament de Química Inorgànica i Orgànica & IQTCUB, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys, 23, 08020 Barcelona, Spain.
المصدر: ACS catalysis [ACS Catal] 2023 Oct 10; Vol. 13 (20), pp. 13672-13678. Date of Electronic Publication: 2023 Oct 10 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101562209 Publication Model: eCollection Cited Medium: Print ISSN: 2155-5435 (Print) NLM ISO Abbreviation: ACS Catal Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Chemical Society, c2011-
مستخلص: Human O -linked β- N -acetylglucosaminidase (hOGA) is one of the two enzymes involved in nuclear and cytoplasmic protein O-GlcNAcylation, an essential post-translational modification. The enzyme catalyzes the hydrolysis of the GlcNAc- O -(Ser/Thr) glycosidic bonds via anchimeric assistance through the 2-acetamido group of the GlcNAc sugar. However, the conformational itinerary of the GlcNAc ring during catalysis remains unclear. Here we report the crystal structure of wild type hOGA in complex with a nonhydrolyzable glycopeptide substrate and elucidate the full enzyme catalytic mechanism using QM/MM metadynamics. We show that the enzyme can bind the substrate in either a chair- or a boat-like conformation, but only the latter is catalytically competent, leading to the reaction products via 1,4 B / 1 S 3 → [ 4 E ] ‡ → 4 C 1 and 4 C 1 → [ 4 E ] ‡ → 1,4 B / 1 S 3 conformational itineraries for the first and second catalytic reaction steps, respectively. Our results reconcile previous experimental observations for human and bacterial OGA and will aid the development of more effective OGA inhibitors for diseases associated with impaired O -GlcNAcylation.
Competing Interests: The authors declare no competing financial interest.
(© 2023 American Chemical Society.)
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تواريخ الأحداث: Date Created: 20231116 Latest Revision: 20240212
رمز التحديث: 20240213
مُعرف محوري في PubMed: PMC10636738
DOI: 10.1021/acscatal.3c02378
PMID: 37969138
قاعدة البيانات: MEDLINE
الوصف
تدمد:2155-5435
DOI:10.1021/acscatal.3c02378