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How aberrant N-glycosylation can alter protein functionality and ligand binding: An atomistic view
Matteo Castelli1, Pengrong Yan2, Anna Rodina2
1Department of Chemistry, University of Pavia, via Taramelli 12, 27100 Pavia, Italy.
Structure (London, England : 1993)
|June 21, 2023
Summary
Aberrant protein conformations drive disease. N-glycosylation of glucose-regulated protein 94 (GRP94) alters its dynamics, offering new therapeutic targets for protein-assembly defects.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Protein-assembly defects and aberrant conformational variants are key in therapeutics.
- Understanding protein conformational dynamics is crucial for inhibitor development.
- Chaperones, like GRP94, are central to protein complex assembly and cellular phenotypes.
Purpose of the Study:
- To investigate how N-glycosylation of glucose-regulated protein 94 (GRP94) affects its internal dynamics and conformational states.
- To explore the impact of N-glycosylation on GRP94's interactions with ATP, synthetic ligands, and other proteins.
- To provide a basis for designing therapeutics targeting disease-associated GRP94 conformations.
Main Methods:
- Integration of computational and experimental approaches.
- Analysis of N-glycosylation site modifications in GRP94.
- Assessment of GRP94's energy landscape and conformational dynamics.
Main Results:
- N-glycosylation actively modulates the energy landscape of GRP94.
- Specific N-glycosylation residues alter GRP94's conformational fitness for ligand and protein interactions.
- Distinct glycosylation variants influence GRP94's conformational states and assembly properties.
Conclusions:
- N-glycosylation is a critical factor in regulating GRP94 conformational dynamics.
- Targeting specific GRP94 glycosylation variants can lead to novel therapeutic strategies.
- This study supports the development of molecules to address GRP94-related disease states.
Keywords:
GRP94aberrant protein conformationsallosterydiseasedrug designdrug selectivityepichaperomesfunctional dynamicsglycosylationpost-translational modificationsprotein assembly mutationsMore Related Videos
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