The net electrostatic potential and hydration of ABCG2 affect substrate transport

Tomoka Gose, Heather M. Aitken, Yao Wang, John Lynch, Evadnie Rampersaud, Yu Fukuda, Medb Wills, Stefanie A. Baril, Robert C. Ford, Anang Shelat, Megan L. O’Mara and John D. Schuetz ()
Additional contact information
Tomoka Gose: St. Jude Children’s Research Hospital
Heather M. Aitken: The University of Queensland, Australia
Yao Wang: St. Jude Children’s Research Hospital
John Lynch: St. Jude Children’s Research Hospital
Evadnie Rampersaud: St Jude Children’s Research Hospital
Yu Fukuda: St. Jude Children’s Research Hospital
Medb Wills: St. Jude Children’s Research Hospital
Stefanie A. Baril: St. Jude Children’s Research Hospital
Robert C. Ford: The University of Manchester
Anang Shelat: St. Jude Children’s Research Hospital
Megan L. O’Mara: The University of Queensland, Australia
John D. Schuetz: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract ABCG2 is a medically important ATP-binding cassette transporter with crucial roles in the absorption and distribution of chemically-diverse toxins and drugs, reducing the cellular accumulation of chemotherapeutic drugs to facilitate multidrug resistance in cancer. ABCG2’s capacity to transport both hydrophilic and hydrophobic compounds is not well understood. Here we assess the molecular basis for substrate discrimination by the binding pocket. Substitution of a phylogenetically-conserved polar residue, N436, to alanine in the binding pocket of human ABCG2 permits only hydrophobic substrate transport, revealing the unique role of N436 as a discriminator. Molecular dynamics simulations show that this alanine substitution alters the electrostatic potential of the binding pocket favoring hydration of the transport pore. This change affects the contact with substrates and inhibitors, abrogating hydrophilic compound transport while retaining the transport of hydrophobic compounds. The N436 residue is also required for optimal transport inhibition of ABCG2, as many inhibitors are functionally impaired by this ABCG2 mutation. Overall, these findings have biomedical implications, broadly extending our understanding of substrate and inhibitor interactions.

Date: 2023
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DOI: 10.1038/s41467-023-40610-5

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