Thomas B Freeman

Publications (2)17.48 Total impact

• Article: Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules

  Xiayang Qiu, Anil Mistry, Mark J Ammirati, Boris A Chrunyk, Ronald W Clark, Yang Cong, Jeffrey S Culp, Dennis E Danley, Thomas B Freeman, Kieran F Geoghegan, [......], Maruja E Lira, David B Lloyd, Katherine M McGrath, Kim J Stutzman-Engwall, Ann K Subashi, Timothy A Subashi, John F Thompson, Ing-Kae Wang, Honglei Zhao, Andrew P Seddon
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  ABSTRACT: Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-Å resolution, revealing a 60-Å-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.
  Nature Structural &#38 Molecular Biology 01/2007; 14(2):106-113. · 12.71 Impact Factor
• Article: Cholesteryl ester transfer protein variants have differential stability but uniform inhibition by torcetrapib.

  David B Lloyd, Maruja E Lira, Linda S Wood, L Kathryn Durham, Thomas B Freeman, Gregory M Preston, Xiayang Qiu, Eliot Sugarman, Peter Bonnette, Anthony Lanzetti, Patrice M Milos, John F Thompson
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  ABSTRACT: Cholesteryl ester transfer protein (CETP) is an important modulator of high density lipoprotein cholesterol in humans and thus considered to be a therapeutic target for preventing cardiovascular disease. The gene encoding CETP has been shown to be highly variable, with multiple single nucleotide polymorphisms responsible for altering both its transcription and sequence. Examining nine missense variants of CETP, we found some had significant associations with CETP mass and high density lipoprotein cholesterol levels. Two variants, Pro-373 and Gln-451, appear to be more stable in vivo, an observation mirrored by partial proteolysis studies performed in vitro. Because these naturally occurring variant proteins are potentially present in clinical populations that will be treated with CETP inhibitors, all commonly occurring haplotypes were tested to determine whether the proteins they encode could be inhibited by torcetrapib, a compound currently in clinical trials in combination with atorvastatin. Torcetrapib behaved similarly with all variants, with no significant differences in inhibition.
  Journal of Biological Chemistry 05/2005; 280(15):14918-22. · 4.77 Impact Factor