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N-Glycosylation-Induced Pathologic Protein Conformations as a Tool to Guide the Selection of Biologically Active Small Molecules.

التفاصيل البيبلوغرافية
العنوان: N-Glycosylation-Induced Pathologic Protein Conformations as a Tool to Guide the Selection of Biologically Active Small Molecules.
المؤلفون: Magni A; Department of Chemistry, University of Pavia, 27100, Pavia, Italy., Sciva C; Department of Chemistry, University of Pavia, 27100, Pavia, Italy.; Institute of Chemical Sciences and Technologies (SCITEC), Italian National Research Council (CNR), 20131, Milano, Italy., Castelli M; Department of Chemistry, University of Pavia, 27100, Pavia, Italy., Digwal CS; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Rodina A; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Sharma S; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Ochiana S; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Patel HJ; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Shah S; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Chiosis G; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Moroni E; Institute of Chemical Sciences and Technologies (SCITEC), Italian National Research Council (CNR), 20131, Milano, Italy., Colombo G; Department of Chemistry, University of Pavia, 27100, Pavia, Italy.
المصدر: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Sep 25; Vol. 30 (54), pp. e202401957. Date of Electronic Publication: 2024 Sep 09.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 9513783 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-3765 (Electronic) Linking ISSN: 09476539 NLM ISO Abbreviation: Chemistry Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Weinheim, Germany : Wiley-VCH
مواضيع طبية MeSH: Molecular Dynamics Simulation* , Protein Conformation*, Glycosylation ; Ligands ; Humans ; Binding Sites ; Protein Processing, Post-Translational ; Quantitative Structure-Activity Relationship ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Membrane Glycoproteins/chemistry ; Membrane Glycoproteins/metabolism
مستخلص: Post-translational modifications such as protein N-glycosylation, significantly influence cellular processes. Dysregulated N-glycosylation, exemplified in Grp94, a member of the Hsp90 family, leads to structural changes and the formation of epichaperomes, contributing to pathologies. Targeting N-glycosylation-induced conformations offers opportunities for developing selective chemical tools and drugs for these pathologic forms of chaperones. We here demonstrate how a specific Grp94 conformation induced by N-glycosylation, identified previously via molecular dynamics simulations, rationalizes the distinct behavior of similar ligands. Integrating dynamic ligand unbinding information with SAR development, we differentiate ligands productively engaging the pathologic Grp94 conformers from those that are not. Additionally, analyzing binding site stereoelectronic properties and QSAR models using cytotoxicity data unveils relationships between chemical, conformational properties, and biological activities. These findings facilitate the design of ligands targeting specific Grp94 conformations induced by abnormal glycosylation, selectively disrupting pathogenic protein networks while sparing normal mechanisms.
(© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)
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معلومات مُعتمدة: R01 CA172546, P01 CA186866, R56 AG061869, RF1 AG071805, R01 AG067598, R01 AG074004, R01 AG072599, P30 CA08748 United States GF NIH HHS; IG 2022 - ID. 27139 Fondazione AIRC per la ricerca sul cancro ETS; IMMUNO-HUB, T4-CN-02, Ministero della Salute; Programma di ricerca CN00000013 Ministero dell'Università e della Ricerca
فهرسة مساهمة: Keywords: Chaperones; Drug design; Molecular dynamics; Post-translational modifications
المشرفين على المادة: 0 (Ligands)
0 (Small Molecule Libraries)
0 (endoplasmin)
0 (Membrane Glycoproteins)
تواريخ الأحداث: Date Created: 20240723 Date Completed: 20240926 Latest Revision: 20240926
رمز التحديث: 20240926
DOI: 10.1002/chem.202401957
PMID: 39042517
قاعدة البيانات: MEDLINE
الوصف
تدمد:1521-3765
DOI:10.1002/chem.202401957