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How Does Agonist and Antagonist Binding Lead to Different Conformational Ensemble Equilibria of the κ-Opioid
Xiaoli An1, Qifeng Bai2, Zhitong Bing2,3
1State Key Laboratory of Applied Organic Chemistry and Department of Chemistry , Lanzhou University , Lanzhou 730000 , China.
Abstract:
The opioid receptors belong to the class A seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). The κ-opioid receptor (KOR) is a subfamily of four opioid receptors. The endogenous peptide and a variety of selective agonists and antagonists of KOR have been developed. The structurally similar ligands at the same site cause completely opposite biological functions and induce different conformational changes. To shed light on the conformation ensembles and conformational dynamics in activation and deactivation processes of KOR, we performed all-atom, long-time Gaussian accelerated molecular dynamics simulation (GaMD) on KOR binding with agonist epoxymorphinan MP1104 and antagonist JDTic, respectively. Our results revealed different conformation ensembles of KOR binding with agonist and with antagonist. Agonist binding stabilizes the active state of key motifs including DYYNM motif and CWxP motif, and biases the conformation equilibria toward the active state. Antagonist binding will not destroy inactive conformation equilibria, by keeping the stable inactive state of these crucial motifs. We found that the inactive apo form of KOR is the most stable state, while the active apo form relaxes readily to inactive state. Our results also revealed a stable intermediate (I), which is attributed to the hydrophobic interactions between Tyr2465.58 and TM6, as well as the steric hindrance of them. Our results not only show the conformation equilibria bias of KOR by binding with agonist and antagonist, but also provide the structural information for the design and discovery of potential ligands with different functions.
Insights
The κ-opioid receptor (KOR) adopts distinct conformations when bound to agonists versus antagonists. Agonists stabilize active states, while antagonists maintain inactive states, influencing KOR
Area of Science:
- Molecular Pharmacology
- Structural Biology
- Computational Chemistry
Background:
- Opioid receptors, including the κ-opioid receptor (KOR), are Class A seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs).
- Selective agonists and antagonists targeting KOR have been developed, yet structurally similar ligands can elicit opposing biological functions.
- Understanding KOR conformational dynamics is crucial for drug design.
Purpose of the Study:
- To investigate the conformational ensembles and dynamics of KOR during activation and deactivation processes.
- To elucidate how agonist and antagonist binding influences KOR conformation.
- To provide structural insights for novel KOR-targeting ligand discovery.
Main Methods:
- All-atom, long-time Gaussian accelerated molecular dynamics simulations (GaMD).
- Simulations performed on KOR in complex with the agonist epoxymorphinan MP1104 and the antagonist JDTic.
- Analysis of conformational changes and stability of key motifs.
Main Results:
- Distinct KOR conformation ensembles were observed for agonist and antagonist binding.
- Agonist binding stabilizes active states of motifs like DYYNM and CWxP, biasing equilibria toward activation.
- Antagonist binding preserves inactive KOR conformations and the stability of crucial motifs.
- The inactive apo KOR form is the most stable, with active forms readily relaxing to the inactive state.
- A stable intermediate state was identified, attributed to specific hydrophobic interactions and steric hindrance.
Conclusions:
- KOR conformation equilibria are significantly biased by agonist versus antagonist binding.
- Agonist binding promotes active KOR conformations, while antagonists maintain inactive states.
- The findings offer valuable structural information for designing KOR ligands with specific functional outcomes.
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