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Updated: May 23, 2026
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Modeling Ligands into Maps Derived from Electron Cryomicroscopy
Published on: July 19, 2024
Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers.
Balananda-Dhurjati K Putcha1, Edward Wright, Joseph S Brunzelle
1University of Tennessee, Knoxville, TN 37996, USA.
Summary
Thyroid hormone receptors (TR) and RXR form heterodimers that regulate gene expression. This study reveals the atomic structure of the TR•T3:RXR•9c complex, explaining negative cooperativity in ligand binding and coactivator recruitment.
Area of Science:
- Molecular Biology
- Structural Biology
- Endocrinology
Background:
- Thyroid hormones (e.g., 3,3',5 triiodo-L-thyronine, T3) are crucial for mammalian development and metabolism.
- Thyroid hormone receptors (TRs) mediate hormone action by binding DNA and recruiting coactivators.
- TRs form heterodimers with other nuclear receptors, such as the 9-cis retinoic acid receptor (RXR), to regulate gene transcription.
Purpose of the Study:
- To determine the atomic resolution structure of the TRα•T3:RXRα•9-cis retinoic acid (9c) ligand binding domain heterodimer complex.
- To investigate the structural basis for allosteric communication and negative cooperativity between T3 and 9c binding pockets.
- To elucidate the mechanism of repression of TR:RXR transactivation by RXR agonists.
Main Methods:
- X-ray crystallography to obtain the atomic structure of the TR•T3:RXR•9c complex at 2.95 Å resolution.
- Hormone binding and dissociation kinetic studies.
- Coactivator binding assays using a steroid receptor coactivator-1 fragment.
Main Results:
- The structure reveals both TR and RXR in active conformations, but TR•T3 exhibits relative disorder within the heterodimer.
- T3 dissociates more rapidly from the TR•T3:RXR•9c complex compared to TR•T3:RXR.
- Coactivator binding affinity is lower for the TR•T3:RXR•9c complex than for TR•T3:RXR, indicating negative cooperativity.
Conclusions:
- The study provides a structural mechanism for the repression of TR:RXR transactivation by RXR agonists.
- Negative cooperativity in ligand binding within TR:RXR heterodimers has significant pharmacological implications, especially given the role of RXR agonists in physiological processes like lipid biosynthesis.
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