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N-Glycosylation-Induced Pathologic Protein Conformations as a Tool to Guide the Selection of Biologically Active Small Molecules.
Magni, Andrea; Sciva, Cristiano; Castelli, Matteo; Digwal, Chander S; Rodina, Anna; Sharma, Sahil; Ochiana, Stefan; Patel, Hardik J; Shah, Smit; Chiosis, Gabriela; Moroni, Elisabetta; Colombo, Giorgio.
Afiliación
  • Magni A; Department of Chemistry, University of Pavia, 27100, Pavia, Italy.
  • Sciva C; Department of Chemistry, University of Pavia, 27100, Pavia, Italy.
  • Castelli M; Institute of Chemical Sciences and Technologies (SCITEC), Italian National Research Council (CNR), 20131, Milano, Italy.
  • Digwal CS; Department of Chemistry, University of Pavia, 27100, Pavia, Italy.
  • 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.
  • Moroni E; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • Colombo G; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Chemistry ; 30(54): e202401957, 2024 Sep 25.
Article en En | MEDLINE | ID: mdl-39042517
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Conformación Proteica / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: Chemistry Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Conformación Proteica / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: Chemistry Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Alemania