The net electrostatic potential and hydration of ABCG2 affect substrate transport
Tomoka Gose1, Heather M Aitken2, Yao Wang1
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
Nature Communications
|August 18, 2023
Summary
The ATP-binding cassette transporter ABCG2 uses residue N436 to distinguish between hydrophilic and hydrophobic substrates. This finding impacts cancer drug resistance and transporter function understanding.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- ABCG2 (ATP-binding cassette transporter G2) is vital for drug absorption and distribution.
- It plays a key role in multidrug resistance in cancer by reducing chemotherapeutic drug accumulation.
- The mechanism by which ABCG2 transports diverse compounds, both hydrophilic and hydrophobic, remains unclear.
Purpose of the Study:
- To elucidate the molecular basis of substrate discrimination by the ABCG2 binding pocket.
- To identify specific residues responsible for differentiating between hydrophilic and hydrophobic substrates.
Main Methods:
- Site-directed mutagenesis was used to substitute a conserved polar residue (N436) with alanine in human ABCG2.
- Molecular dynamics simulations were performed to analyze changes in the binding pocket's electrostatic potential and hydration.
- Transport assays were conducted to assess the effect of the mutation on substrate and inhibitor interactions.
Main Results:
- Substitution of N436 with alanine specifically enabled transport of hydrophobic substrates while abrogating hydrophilic substrate transport.
- Molecular dynamics simulations revealed that the N436 mutation alters the binding pocket's electrostatic potential, favoring pore hydration.
- This N436 residue is critical for the efficacy of many ABCG2 inhibitors, with the mutation impairing inhibitor function.
Conclusions:
- The N436 residue acts as a key discriminator for substrate transport in ABCG2.
- Understanding N436's role provides insights into ABCG2's transport mechanism and substrate specificity.
- These findings have significant biomedical implications for cancer therapy and drug development, particularly concerning multidrug resistance.
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