The net electrostatic potential and hydration of ABCG2 affect substrate transport

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.

The Human ABCG2 Transporter Relies on a Triple-Gated Translocation Channel for Multidrug Efflux

“…Hence, the data strongly suggest that these two residues engage in both substrate and inhibitor recognition in ABCG2. The data are consistent with a recent publication indicating that N436 act as a discriminator for substrates and inhibitors 43 . A conservation analysis (Fig.…”

“…1). Alanine-substitution of residues around the binding pocket of ABCG2 can still facilitate the efflux of hydrophobic substrates such as pheophorbide A 43 . Remarkably, pheophorbide A showed a better binding score in the central cavity (-11.7) than mitoxantrone (-8.1) (Fig.…”

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin

“…Thus, a conformational change induced by the inhibitor is needed to prevent the doxorubicin efflux and reverse chemotherapy resistance. The binding of an inhibitor to Asn436 is known to stabilized the inward-facing state of ABCG2 which inhibits the transport of hydrophilic ABCG2 substrates [48]. Even if the docking of our carborane-based compounds predicted a hydrogen bond towards Asn436, it seems not to influence the conformational change of the protein.…”

“…An inhibitor, located between Phe439-Phe439 in the inward-facing state of ABCG2 is described as the most common inhibition mechanism preventing the conformational change to the outward-facing state. As speculated for lapatinib [48], a potential inhibition of the clamp by DMQCc and DMQCd through π-π stacking can be suggested [32]. In contrast, doxorubicin binds to a lateral pocket within the inner binding pocket.…”

The Effect of Intermolecular Interactions on the Dissolution Property of Aripiprazole

“…The MSEP plot is quite suitable for the study of intermolecular interaction sites due to the ability to clearly show the distribution of electrostatic sites on the surface of the molecule in different colors. − So, the MESPs of the APZ molecules and 11 solvent molecules were calculated and visualized, and the results are listed in Figure .…”