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.
Highlights
ABCG2 mediated membrane transport is an important mechanism for the elimination of several toxic substrates from the cell
Cryo-electron microscopy studies revealed that the TM helices in ABCG2 are short, bringing the nucleotide-binding domains (NBDs) in close proximity to the intracellular leaflet of the membrane bilayer (Fig. S1)
The NBD and TMD are connected by a socalled linker region, which involves a V-shaped α-helical region surrounded by highly dynamic segments not resolved in any of the Cryo-electron microscopy (cryo-EM) structures [25, 26]
Summary
ABCG2 mediated membrane transport is an important mechanism for the elimination of several toxic substrates from the cell. Cryo-electron microscopy (cryo-EM) studies revealed that the TM helices in ABCG2 are short, bringing the nucleotide-binding domains (NBDs) in close proximity to the intracellular leaflet of the membrane bilayer (Fig. S1). The amphipathic elbow helix, called connecting helix or TH1a in ABCG proteins and the short intracellular loops called coupling helices, play an important role in coupling the conformational changes between the NBDs and TMDs. The large extracellular loop (EL3), which contain intra- and intermolecular disulfide bridges, has been demonstrated to interact with all other extracellular loops and the reentrant, creek-forming G-loop (Fig. S1) [27]. The potential role of the unresolved, highly dynamic segments is currently unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
