title: Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules.
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-A resolution, revealing a 60-A-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.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06430, USA. xiayang.qiu@pfizer.com
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.forename: Anil
authors.initials: A
authors.lastname: Mistry
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ammirati
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Clark
authors.forename: Yang
authors.initials: Y
authors.lastname: Cong
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Culp
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Freeman
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Geoghegan
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Griffor
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hawrylik
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Hayward
authors.forename: Preston
authors.initials: P
authors.lastname: Hensley
authors.forename: Lise R
authors.initials: LR
authors.lastname: Hoth
authors.forename: George A
authors.initials: GA
authors.lastname: Karam
authors.forename: Maruja E
authors.initials: ME
authors.lastname: Lira
authors.forename: David B
authors.initials: DB
authors.lastname: Lloyd
authors.forename: Katherine M
authors.initials: KM
authors.lastname: McGrath
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Stutzman-Engwall
authors.forename: Ann K
authors.initials: AK
authors.lastname: Subashi
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Subashi
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Ing-Kae
authors.initials: IK
authors.lastname: Wang
authors.forename: Honglei
authors.initials: H
authors.lastname: Zhao
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Seddon
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry* / Q000235:genetics; D002788:Cholesterol Esters / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000737:chemistry*; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D014280:Triglycerides / Q000737:chemistry*
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008024:Ligands; D010713:Phosphatidylcholines; D014280:Triglycerides