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  Dynamics of cholesterol exchange in the oxysterol binding protein family

Canagarajah, B. J., Hummer, G., Prinz, W. A., & Hurley, J. H. (2008). Dynamics of cholesterol exchange in the oxysterol binding protein family. Journal of Molecular Biology, 378(3), 737-748. doi:10.1016/j.jmb.2008.01.075.

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 Creators:
Canagarajah, Bertram J.1, Author
Hummer, Gerhard2, Author           
Prinz, William A.1, Author
Hurley, James H.1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA, ou_persistent22              

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Free keywords: Binding Sites, Cholesterol, Computer Simulation, Crystallography, X-Ray, Hydrogen Bonding, Membrane Proteins, Receptors, Steroid, Saccharomyces cerevisiae Proteins, Thermodynamics
 Abstract: The oxysterol-binding protein-related protein (ORP) family is essential to sterol transfer and sterol-dependent signal transduction in eukaryotes. The crystal structure of one ORP family member, yeast Osh4, is known in apo and sterol-bound states. In the bound state, a 29 residue N-terminal lid region covers the opening of the cholesterol-binding tunnel, preventing cholesterol exchange. Equilibrium and steered molecular dynamics (MD) simulations of Osh4 were carried out to characterize the mechanism of cholesterol exchange. While most of the structural core was stable during the simulations, the lid was partly opened in the apo equilibrium MD simulation. Helix alpha 7, which undergoes the largest conformational change in the crystallized bound and apo states, is conformationally coupled to the opening of the lid. The movement of alpha 7 helps create a docking site for donor or acceptor membranes in the open state. In the steered MD simulations of cholesterol dissociation, we observed complete opening of the lid covering the cholesterol-binding tunnel. Cholesterol was found to exit the binding pocket in a step-wise process involving (i) the breaking of water-mediated hydrogen bonds and van der Waals contacts within the binding pocket, (ii) opening of the lid covering the binding pocket, and (iii) breakage of transient cholesterol contacts with the rim of the pocket and hydrophobic residues on the interior face of the lid.

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Language(s): eng - English
 Dates: 2007-12-042007-10-052008-01-232008-02-042008-05
 Publication Status: Issued
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.jmb.2008.01.075
BibTex Citekey: canagarajah_dynamics_2008
 Degree: -

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Title: Journal of Molecular Biology
  Other : J Mol Biol
Source Genre: Journal
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Publ. Info: London : Academic Press
Pages: - Volume / Issue: 378 (3) Sequence Number: - Start / End Page: 737 - 748 Identifier: ISSN: 0022-2836
CoNE: https://pure.mpg.de/cone/journals/resource/954922646042