Abstract
We present a 3D model of the four transmembrane (TM) helical regions of bilitranslocase (BTL), a structurally uncharacterized protein that transports organic anions across the cell membrane. The model was computed by considering helix-helix interactions as primary constraints, using Monte Carlo simulations. The interactions between the TM2 and TM3 segments have been confirmed by Förster resonance energy transfer (FRET) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy, increasing our confidence in the model. Several insights into the BTL transport mechanism were obtained by analyzing the model. For example, the observed cis-trans Leu-Pro peptide bond isomerization in the TM3 fragment may indicate a key conformational change during anion transport by BTL. Our structural model of BTL may facilitate further studies, including drug discovery.
Highlights
Understanding the molecular mechanisms underlying the passage of ions and small molecules through biological membranes is a fundamental aspect of cell physiology
Of strong interest as potential drug targets are the organic anion transporter family proteins (OATPs), due to their capacity to serve as tumor biomarkers and effective cancer drug transporters [1,2]
Charged residues are present at the boundaries, our previous studies have shown that these boundary residues are contained within the lipid bilayer during the MD simulations, and do not show any translational motion along y-axis [16,17]. These results were confirmed by nuclear magnetic resonance (NMR) spectroscopy [16,17]
Summary
Understanding the molecular mechanisms underlying the passage of ions and small molecules through biological membranes is a fundamental aspect of cell physiology. This knowledge is crucial for analyzing disease associations, for identifying potential drug targets, and for improving safety and efficacy of new or existing drugs. Transmembrane proteins provide key means of molecular transport through the cell membrane. They are extensively studied as potential drug targets. Of strong interest as potential drug targets are the organic anion transporter family proteins (OATPs), due to their capacity to serve as tumor biomarkers and effective cancer drug transporters [1,2]. The physiological expression patterns of the OATPs are PLOS ONE | DOI:10.1371/journal.pone.0135455 August 20, 2015
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