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Structural basis of tropifexor as a potent and selective agonist of farnesoid X receptor

Longying Jiang1, Desheng Xiao1, Yubin Li1

  • 1Department of Pathology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Biochemical and Biophysical Research Communications
|October 30, 2020
PubMed

Insights

Tropifexor effectively treats liver diseases by targeting Farnesoid X receptor (FXR). This study reveals its precise binding mechanism and high selectivity for FXR over TGR5, explaining its therapeutic potential.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Farnesoid X receptor (FXR) is a key therapeutic target for liver diseases like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).
  • Tropifexor, a potent non-steroidal FXR agonist, is in Phase II clinical trials for PBC, showing promise in improving liver disease markers and reducing side effects.
  • The molecular basis for tropifexor's potency and selectivity remains to be elucidated.

Purpose of the Study:

  • To elucidate the molecular mechanism behind tropifexor's high potency and selectivity as an FXR agonist.
  • To understand how tropifexor binds to the FXR ligand-binding domain (LBD).
  • To investigate the structural basis for tropifexor's selectivity towards FXR over TGR5.

Main Methods:

  • Isothermal titration calorimetry (ITC) was used to measure the binding affinity between FXR and tropifexor.
  • X-ray crystallography determined the 2.7 Å resolution crystal structure of the FXR/tropifexor complex.
  • Structural comparisons and superposition analyses were performed with other FXR/agonist and TGR5/tropifexor structures.

Main Results:

  • ITC assays confirmed the binding affinity of tropifexor to FXR.
  • The crystal structure revealed the specific binding mode of tropifexor within the FXR-LBD, highlighting conformational changes.
  • Structural superposition with TGR5 suggested steric hindrance as a potential reason for tropifexor's lack of activity against TGR5.

Conclusions:

  • The study provides molecular insights into tropifexor's binding to FXR-LBD.
  • The findings explain tropifexor's high selectivity for FXR compared to TGR5.
  • This understanding can guide the development of FXR-targeted therapies for liver disorders.
Keywords:
Crystal structureFarnesoid X receptorLiver diseasesNonsteroidal agonistsTropifexor

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