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Papers In Press, published online ahead of print September 21, 2006
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Biochemistry & Molecular Biology, University of Chicago, Chicago, IL 60637
Corresponding Author: roux{at}uchicago.edu
StAR-related lipid transfer (StART) domains are ubiquitously involved in intracellular lipid transport and metabolism and other cell-signaling events. In this work, we employ a flexible docking algorithm, comparative modeling and molecular dynamics simulations, to generate plausible three-dimensional atomic models of the StART domains of human MLN64 and StAR proteins in complex with cholesterol. Our results show that cholesterol can adopt a similar conformation in the binding cavity in both cases, and that the main contribution to the protein-ligand interaction energy derives from hydrophobic contacts. However, hydrogen-bonding and water-mediated interactions appear to be important in the fine-tuning of the binding affinity and the position of the ligand. In order to gain insights into the mechanism of binding, we carry out steered molecular dynamics simulations where cholesterol is gradually extracted from within the StAR model. These simulations indicate that a transient opening of loop O1 may be sufficient for uptake and release, and also reveal a pathway of intermediate states involving residues known to be crucial for StAR activity. Based on these observations, we suggest specific mutagenesis targets for binding studies of cholesterol and its derivatives that could improve our understanding of the structural determinants for ligand binding by sterol carrier proteins.
Revised on September 18, 2006
Accepted on September 21, 2006
Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol
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