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

Nature Structural & Molecular Biology volume 14, pages 106–113 (2007)Cite this article

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.

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Figure 1: Overall structure of CETP.
Figure 2: Bound lipids and the tunnel.
Figure 3: Stereo view of the lipid-binding sites.
Figure 4: The mobile helix X and the Ω1 flap.
Figure 5: Concave surface and HDL binding.
Figure 6: Proposed mechanism for CETP-mediated heteroexchange.

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Acknowledgements

We thank the staffs in the X-ray group and synchrotrons for assistance in data collection, G. Andrews, M. Bamberger, L. Morehouse, D. Perry, R. Ruggeri, K. Ranney, I. Reininger, M. Tu and P. Zagouras for insightful discussions and S. Liu, J. Boyd, D. Cunningham, T. Dickinson, J. Duerr, B. King, T. Lanzetti, W. Lin, P. Loulakis, M. Mansour, A. McColl, T. McLellan, F. Rajamohan, M. Rosner, M. Tardie and Z. Xie for supporting work.

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  1. Pfizer Global Research and Development, Eastern Point Road, Groton, 06430, Connecticut, USA

    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, Matthew C Griffor, Steven J Hawrylik, Cheryl M Hayward, Preston Hensley, Lise R Hoth, George A Karam, 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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Contributions

M.C.G., S.J.H., T.A.S., I.-K.W., H.Z., K.M.M., K.J.S.-E., T.B.F., L.R.H., K.F.G., Y.C., G.A.K., B.A.C., J.S.C. and A.K.S. provided key reagents. A.M., M.J.A. and D.E.D. crystallized the proteins. X.Q. solved the structure. M.E.L., D.B.L., J.F.T. and R.W.C. contributed to mutagenesis and assays. X.Q., P.H., C.M.H. and A.P.S coordinated the research and data review. X.Q., J.F.T., K.F.G. and A.P.S. wrote the paper.

Corresponding author

Correspondence to Xiayang Qiu.

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The authors are employees of Pfizer Inc., which develops and markets medicines to treat cardiovascular disease.

Supplementary information

Supplementary Fig. 1

Structure-based alignment of human CETP species and BPI. (PDF 436 kb)

Supplementary Data

Additional methods and data. (PDF 165 kb)

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Qiu, X., Mistry, A., Ammirati, M. et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol 14, 106–113 (2007). https://doi.org/10.1038/nsmb1197

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