Conformational changes in the nucleotide-binding domains of P-glycoprotein induced by ATP hydrolysis

Sepehr Dehghani-Ghahnaviyeh, Karan Kapoor, Emad Tajkhorshid

Research output: Contribution to journalArticlepeer-review


P-glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological importance. Pgp nucleotide-binding domains (NBDs) drive the transport cycle through ATP binding and hydrolysis. We use molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in NBDs. Five systems, including all possible ATP/ADP combinations in the NBDs and the APO system, are simulated. ATP/ADP exchange induces conformational changes mostly within the conserved signature motif of the NBDs, resulting in relative orientational changes in the NBDs. Nucleotide removal leads to additional orientational changes in the NBDs, allowing their dissociation. Furthermore, we capture putative hydrolysis-competent configurations in which the conserved glutamate in the Walker-B motif acts as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.

Original languageEnglish (US)
Pages (from-to)735-749
Number of pages15
JournalFEBS Letters
Issue number6
Early online dateNov 7 2020
StatePublished - Mar 2021


  • ABC transporters
  • ATP hydrolysis
  • conformational changes
  • molecular dynamics
  • P-glycoprotein

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biophysics
  • Structural Biology
  • Biochemistry
  • Cell Biology


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