How aberrant N-glycosylation can alter protein functionality and ligand binding: An atomistic view Journal Article
| Authors: | Castelli, M.; Yan, P.; Rodina, A.; Digwal, C. S.; Panchal, P.; Chiosis, G.; Moroni, E.; Colombo, G. |
| Article Title: | How aberrant N-glycosylation can alter protein functionality and ligand binding: An atomistic view |
| Abstract: | Protein-assembly defects due to an enrichment of aberrant conformational protein variants are emerging as a new frontier in therapeutics design. Understanding the structural elements that rewire the conformational dynamics of proteins and pathologically perturb functionally oriented ensembles is important for inhibitor development. Chaperones are hub proteins for the assembly of multiprotein complexes and an enrichment of aberrant conformers can affect the cellular proteome, and in turn, phenotypes. Here, we integrate computational and experimental tools to investigte how N-glycosylation of specific residues in glucose-regulated protein 94 (GRP94) modulates internal dynamics and alters the conformational fitness of regions fundamental for the interaction with ATP and synthetic ligands and impacts substructures important for the recognition of interacting proteins. N-glycosylation plays an active role in modulating the energy landscape of GRP94, and we provide support for leveraging the knowledge on distinct glycosylation variants to design molecules targeting GRP94 disease-associated conformational states and assemblies. © 2023 Elsevier Ltd |
| Keywords: | protein conformation; protein binding; drug design; drug selectivity; chemistry; ligand; glycosylation; ligands; chaperone; disease; molecular chaperones; grp94; post-translational modifications; functional dynamics; allostery; epichaperomes; aberrant protein conformations; protein assembly mutations |
| Journal Title: | Structure |
| Volume: | 31 |
| Issue: | 8 |
| ISSN: | 0969-2126 |
| Publisher: | Cell Press |
| Date Published: | 2023-08-01 |
| Start Page: | 987 |
| End Page: | 1004.e8 |
| Language: | English |
| DOI: | 10.1016/j.str.2023.05.017 |
| PUBMED: | 37343552 |
| PROVIDER: | scopus |
| PMCID: | PMC10526633 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Gabriela Chiosis -- Source: Scopus |
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