The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations Tamás Nagy1 · Ágota Tóth1 · Ágnes Telbisz2 · Balázs Sarkadi1,2 · Hedvig Tordai1 · Attila Tordai3 · Tamás Hegedűs1 Received: 26 May 2020 / Revised: 1 September 2020 / Accepted: 15 September 2020 © The Author(s) 2020
Abstract Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions. Keywords ABCG2 · Multidrug transport · Molecular dynamics · Cholesterol regulation
Introduction ABCG2 mediated membrane transport is an important mechanism for the elimination of several toxic substrates from the cell. Localization of this important ABC transporter in all-important tissue barriers (apical surface of hepatocytes, renal cells, blood–brain barrier etc.) and stem cells renders ABCG2 a key factor in drug resistance and uric acid elimination. ABCG2 is also crucial in the pharmacokinetics of several compounds [1–3] which is highlighted by the fact Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03651-3) contains supplementary material, which is available to authorized users. * Tamás Hegedűs [email protected] 1
Department of Biophysics and Radiation Biology, Semmelweis University, Tuzolto u. 37‑47, 1094 Budapest, Hungary
2
Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary
3
Department of Transfusion Medicine, Semmelweis University, Nagyvarad ter 4, 1089 Budapest, Hungary
that the US Food and Drug Administration and the European Medicines Agency list ABCG2 among the transporters to be investigated for pharmacokinetics and drug-drug interactions [4, 5]. Experimental data showed that ABCG2 can handle substrates with a wide variety in size and polarity [2, 6, 7]. Uric acid is a small and amphiphilic physi
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