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

Autor: 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.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Sep 25; Vol. 30 (54), pp. e202401957. Date of Electronic Publication: 2024 Sep 09.
DOI: 10.1002/chem.202401957
Abstrakt: 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.)
Databáze: MEDLINE
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