Tumor-acquired somatic mutation affects conformation to abolish ABCG2-mediated drug resistance

Tomoka Gose, Ali Rasouli, Sepehr Dehghani-Ghahnaviyeh, Po Chao Wen, Yao Wang, John Lynch, Yu Fukuda, Talha Shafi, Robert C. Ford, Emad Tajkhorshid, John D. Schuetz

Research output: Contribution to journalArticlepeer-review

Abstract

ABCG2 is an important ATP-binding cassette transporter impacting the absorption and distribution of over 200 chemical toxins and drugs. ABCG2 also reduces the cellular accumulation of diverse chemotherapeutic agents. Acquired somatic mutations in the phylogenetically conserved amino acids of ABCG2 might provide unique insights into its molecular mechanisms of transport. Here, we identify a tumor-derived somatic mutation (Q393K) that occurs in a highly conserved amino acid across mammalian species. This ABCG2 mutant seems incapable of providing ABCG2-mediated drug resistance. This was perplexing because it is localized properly and retained interaction with substrates and nucleotides. Using a conformationally sensitive antibody, we show that this mutant appears “locked” in a non-functional conformation. Structural modeling and molecular dynamics simulations based on ABCG2 cryo-EM structures suggested that the Q393K interacts with the E446 to create a strong salt bridge. The salt bridge is proposed to stabilize the inward-facing conformation, resulting in an impaired transporter that lacks the flexibility to readily change conformation, thereby disrupting the necessary communication between substrate binding and transport.

Original languageEnglish (US)
Article number101066
JournalDrug Resistance Updates
Volume73
DOIs
StatePublished - Mar 2024

Keywords

  • ABC transporter
  • ABCG2
  • Cancer
  • Conformational changes
  • Genetic variant

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Cancer Research
  • Infectious Diseases
  • Pharmacology (medical)

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