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Peer-reviewedCC BY-NC-NDMagnetic Resonance Letters

Uncovering a cryptic allosteric hub governing energy landscape plasticity within the Nur77 ligand-binding domain

  • Lang Chen1
  • Jiawen Chen2
  • Conggang Li2
  • Ling Jiang3
  • Yixiang Liu3
  1. 1National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, 430071, China; University of Chinese Academy of Sciences, Beijing, 100049, China
  2. 2National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, 430071, China
  3. 3National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, 430071, China; Corresponding author.
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Abstract

Nur77 (NR4A1) is an orphan nuclear receptor whose allosteric mechanism departs fundamentally from that of classical nuclear receptors. Its ligand-binding pocket is constitutively occupied by endogenous hydrophobic side chains, obscuring the structural and allosteric basis of its conformational regulation. As a result, drug design targeting Nur77 has always posed greater challenges. Using NMR spectroscopy, we identified two conformational substates defined by a pocket enclosed by the H1–H3 loop of the ligand-binding domain. These substates interconvert slowly beyond the NMR detection timescale, reflecting a substantial free energy barrier. Solvent-induced isotope shift (SIIS) experiments reveal differential hydrophobic exposure of these two substates, with the minor substate displaying enhanced solvent accessibility. Integrating multiple sequence alignment (MSA) with mutational dissection, we identified a network of long-range weak interactions that acts as a cryptic allosteric hub governing substate equilibrium. Notably, the two substates exhibit distinct ligand-binding affinities, implying functional specialization. Therefore, this study reveals a non-classical allosteric framework of Nur77, providing a structural basis for the design of drugs that target allosteric regulation.

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Cite

BibTeXRIS
BibTeX
@article{chen2026uncovering,
  title = {{Uncovering a cryptic allosteric hub governing energy landscape plasticity within the Nur77 ligand-binding domain}},
  author = {Lang Chen and Jiawen Chen and Conggang Li and Ling Jiang and Yixiang Liu},
  journal = {Magnetic Resonance Letters},
  year = {2026},
  month = oct,
  doi = {10.1016/j.mrl.2026.200312},
  url = {https://doi.org/10.1016/j.mrl.2026.200312},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Uncovering a cryptic allosteric hub governing energy landscape plasticity within the Nur77 ligand-binding domain
AU  - Lang Chen
AU  - Jiawen Chen
AU  - Conggang Li
AU  - Ling Jiang
AU  - Yixiang Liu
PY  - 2026
DA  - 2026/10/15
JO  - Magnetic Resonance Letters
DO  - 10.1016/j.mrl.2026.200312
UR  - https://doi.org/10.1016/j.mrl.2026.200312
AB  - Nur77 (NR4A1) is an orphan nuclear receptor whose allosteric mechanism departs fundamentally from that of classical nuclear receptors. Its ligand-binding pocket is constitutively occupied by endogenous hydrophobic side chains, obscuring the structural and allosteric basis of its conformational regulation. As a result, drug design targeting Nur77 has always posed greater challenges. Using NMR spectroscopy, we identified two conformational substates defined by a pocket enclosed by the H1–H3 loop of the ligand-binding domain. These substates interconvert slowly beyond the NMR detection timescale, reflecting a substantial free energy barrier. Solvent-induced isotope shift (SIIS) experiments reveal differential hydrophobic exposure of these two substates, with the minor substate displaying enhanced solvent accessibility. Integrating multiple sequence alignment (MSA) with mutational dissection, we identified a network of long-range weak interactions that acts as a cryptic allosteric hub governing substate equilibrium. Notably, the two substates exhibit distinct ligand-binding affinities, implying functional specialization. Therefore, this study reveals a non-classical allosteric framework of Nur77, providing a structural basis for the design of drugs that target allosteric regulation.
SN  - 2772-5162
SN  - 2097-0048
ER  -