Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
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Updated: Sep 1, 2025
High Precision FRET at Single-molecule Level for Biomolecule Structure Determination
Published on: May 13, 2017
Giulia D'Arrigo1, Ida Autiero2,3, Eleonora Gianquinto1
1Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Turin, Italy.
Abstract:
Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases, such as cancer, inflammation, and metabolic disorders. They share a common structural organization composed of five domains, of which the ligand-binding domain (LBD) can adopt different conformations in response to substrate, agonist, and antagonist binding, leading to distinct transcription effects. A key feature of NRs is, indeed, their intrinsic dynamics that make them a challenging target in drug discovery. This work aims to provide a meaningful investigation of NR structural variability to outline a dynamic profile for each of them. To do that, we propose a methodology based on the computation and comparison of protein cavities among the crystallographic structures of NR LBDs. First, pockets were detected with the FLAPsite algorithm and then an "all against all" approach was applied by comparing each pair of pockets within the same sub-family on the basis of their similarity score. The analysis concerned all the detectable cavities in NRs, with particular attention paid to the active site pockets. This approach can guide the investigation of NR intrinsic dynamics, the selection of reference structures to be used in drug design and the easy identification of alternative binding sites.
Insights
Nuclear receptors (NRs) are crucial for disease and drug discovery. This study analyzes NR structural variability using protein cavities to map their dynamic profiles for better drug design.
Area of Science:
- Molecular Biology
- Structural Biology
- Pharmacology
Background:
- Nuclear receptors (NRs) are transcription factors implicated in various diseases, including cancer, inflammation, and metabolic disorders.
- The ligand-binding domain (LBD) of NRs exhibits conformational flexibility, influencing transcriptional activity and posing challenges for drug discovery.
- Understanding NR dynamics is crucial for developing targeted therapeutics.
Purpose of the Study:
- To investigate the structural variability of Nuclear Receptors (NRs).
- To establish a dynamic profile for each NR.
- To aid in drug discovery by understanding NR structural dynamics and identifying potential binding sites.
Main Methods:
- Computation and comparison of protein cavities within NR ligand-binding domains (LBDs) across crystallographic structures.
- Utilized the FLAPsite algorithm for pocket detection.
- Employed an 'all against all' comparison of pockets within NR sub-families based on similarity scores.
Main Results:
- Successfully mapped the structural variability of NR LBDs.
- Characterized distinct dynamic profiles for different NRs.
- Identified key active site pockets and potential alternative binding sites.
Conclusions:
- The proposed methodology effectively outlines NR dynamic profiles by analyzing protein cavities.
- This approach can guide the selection of reference structures for drug design.
- Facilitates the identification of alternative binding sites for therapeutic intervention.
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