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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations

Selom K Doamekpor1, Panfeng Peng2, Ruo Xu2

  • 1Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

Acta Crystallographica. Section F, Structural Biology Communications
|March 30, 2023
PubMed

Insights

Prostate cancer drug resistance is linked to androgen receptor (AR) mutations. Structural studies reveal how AR mutations like F877L alter AR LBD conformation, impacting drug efficacy and resistance mechanisms.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Oncology

Background:

  • Mutations in the androgen receptor (AR) ligand-binding domain (LBD) are a key mechanism of resistance to prostate cancer therapies.
  • Specific AR mutations, such as F877L, can transform AR antagonists into agonists, diminishing treatment effectiveness.

Purpose of the Study:

  • To investigate the structural basis of AR antagonist resistance, focusing on the F877L mutation and its impact on AR LBD conformation and ligand binding.
  • To characterize the structural and functional effects of a quadruple AR LBD mutation (L702H/H875Y/F877L/T878A) in complex with AR antagonists.

Main Methods:

  • Crystallography was used to determine the structure of the quadruple AR LBD mutant bound to dihydrotestosterone (DHT).
  • Expression of AR LBD mutants in Escherichia coli was optimized for structural studies.
  • Conformational analysis of the AR LBD was performed to understand the impact of mutations on ligand-binding pocket dynamics.

Main Results:

  • The quadruple AR LBD mutation (L702H/H875Y/F877L/T878A) facilitated increased soluble expression of the AR LBD in complex with the antagonist pruxelutamide.
  • The crystal structure revealed a partially open AR LBD conformation in the quadruple mutant bound to DHT, characterized by alterations in the H11-H12 loop and Leu881.
  • This conformational change expands the ligand-binding site, suggesting a mechanism for altered ligand interactions and resistance.

Conclusions:

  • Structural variability within the AR LBD, driven by mutations like L702H and F877L, significantly influences ligand binding.
  • Understanding these structural changes is crucial for developing next-generation AR antagonists that overcome resistance mechanisms in prostate cancer.
Keywords:
COVID-19DHTandrogen receptorsdrug resistanceenzalutamideligand-binding domainprostate cancerpruxelutamide

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