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Cyclopamine modulates smoothened receptor activity in a binding position dependent manner.

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Cyclopamine acts as a SMO agonist at the CRD and antagonist at the TMD. Molecular simulations reveal how cyclopamine binding to specific SMO domains regulates Hedgehog signaling and cholesterol transport.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • Cyclopamine exhibits dual activity as a Smoothened (SMO) receptor agonist at the Cysteine-Rich Domain (CRD) and antagonist at the Transmembrane Domain (TMD).
  • Experimental study of cyclopamine's site-specific effects requires mutations in other domains, highlighting the critical role of simulations for understanding wild-type (WT) SMO activity.

Purpose of the Study:

  • To investigate the dynamic interactions of cyclopamine with different domains of WT SMO.
  • To elucidate the molecular mechanisms underlying cyclopamine's domain-specific agonistic and antagonistic activities.
  • To understand how cyclopamine modulates Hedgehog signaling and cholesterol transport through SMO.

Main Methods:

  • Utilized multi-millisecond aggregate Molecular Dynamics (MD) simulations.
  • Applied Markov state models and machine learning techniques to analyze simulation data.
  • Explored the dynamic behavior of cyclopamine's interactions with CRD and TMD of WT SMO.

Main Results:

  • Binding to CRD showed higher active state population, a lower free energy barrier (~2 kcal/mol), and an expanded hydrophobic tunnel, consistent with agonistic behavior.
  • Binding to TMD resulted in a higher inactive state population, a greater free energy barrier (~4 kcal/mol), and a restricted hydrophobic tunnel, indicating antagonistic behavior.
  • Simultaneous binding to both sites led to a slightly larger inactive population and an increased free energy barrier (~3.5 kcal/mol), demonstrating a weak overall antagonistic effect.

Conclusions:

  • Cyclopamine's binding to specific SMO domains dictates its functional outcome, acting as an agonist at CRD and an antagonist at TMD.
  • These domain-specific modulations by cyclopamine are crucial for regulating Hedgehog signaling pathways.
  • The study provides insights into how cyclopamine influences cholesterol transport via SMO.