Saptaparna Pal, Amity University Kolkata
The ATP binding cassette (ABC) transporter ABCG2, also known as breast cancer resistance protein is expressed in many tissues and tissue barriers, including blood-brain, blood-testis, and maternal-fetal barriers. It transports endogenous substrates such as estrone 3-sulfate and uric acid and also removes cytotoxic and endogenous compounds from cells. ABCG2 actively transports chemically distinct but mostly hydrophobic compounds by recognizing them, many of which are polycyclic and have a relatively flat shape.
The pharmacokinetics of drugs has been affected by ABCG2 which is an ATP binding cassette (ABC) transporter that contributes to multidrug resistance of cancer cells. The interaction of ABCG2 with the endogenous substrate estrone 3-sulfate (EIS) has been illuminated at a structural level, although the recognition and recruitment of exogenous compounds are not understood properly in a sufficiently high resolution. Topotecan is a topoisomerase I initiator that is used to treat ovarian, cervical, and small cell lung cancer. Mitoxantrone is a topoisomerase II inhibitor that is used to treat multiple sclerosis and leukemia. Tariquidar is an anthranilate derivative that originally acts as an ABCG1 inhibitor. The 3 cryo-EM structures of nanodisc-reconstituted include anticancer drugs like tariquidar, topotecan, and mitoxantrone to which the human ABCG2 bounds.
To facilitate structural insight at high resolution, Fab fragments of the ABCG2 specific monoclonal antibody SD3 are used, which binds to the external side of the transporter but does not interfere with drug-influenced stimulation of ATPase activity. It has been observed that the binding pocket of ABCG2 can accommodate a single tariquidar molecule in a C-shaped configuration, alike or similar to one of the two tariquidar molecules that bound to ABCB1 where tariquidar behaves as an inhibitor. Single copies of topotecan and mitoxantrone bound between key phenylalanine residues were also found. The functional living of two residues in the binding pocket, F439 and N436 was confirmed by mutagenesis experiments. The substrate also retains some mobility in the drug-binding pocket of ABCG2. A correlation between substrate binding and reduced dynamics of the nucleotide-binding domains (NBDs) were found using 3D variability analysis, suggesting a structural explanation for drug-induced ATPase stimulation.
The accommodation of drugs in the binding pocket of ABCG2 and its residues contributes to drug recognition. It is demonstrated that substrates are not immobilized as firmly as inhibitors, but instead appear to be shifting in the binding cavity. After analyzing the structural variability between the single particles contributing to the 3D reconstructions, it was found that the structural flexibility of the nucleotide-binding domains is lessened by substrate binding, although the substrate maintains some potency inside the drug-binding pocket. The results provide a basis for understanding drug ABCG2 interactions and for the future development and enhancement of modulators and inhibitors.
Also read: Exosomes predicted to carry out protein secretion
References:
- Julia Kowal, Dongchun Ni, Scott M. Jackson, Ioannis Manolaridis, Henning Stahlberg, Kaspar P. Locher, Structural Basis of Drug Recognition by the Multidrug Transporter ABCG2, Journal of Molecular Biology, Volume 433, Issue 13, 2021, 166980, ISSN 0022-2836, https://doi.org/10.1016/j.jmb.2021.166980.
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