Sandbox 215

Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein which is mainly synthesized in the liver, but also in the intestine, spleen and adrenal glands. In the plasma, CETP is implicated in the transport of cholesteryl esters from the atheroprotective high-density lipoproteins (HDL) to the atherogenic lower-density lipoproteins (LDL). CETP also mediates the transport of triglycerides from LDL to HDL. The cristal structure of CETP, in complex with four bound lipid molecules at 2,2 Å resolution shows a long tunnel traversing the core of the molecule. This tunnel has two large openings allowing lipids access.

spinqualitylabelsall models PDB ID 2obd Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
2obd, resolution 2.10Å ()
Ligands:	, , , , , , ,
Gene:	CETP (Homo sapiens)
Structural annotation: Resources: InterPro : Ipr001124 Pfam : PF02886, PF01273 UniProt : Q53YZ1
Functional annotation: Molecular function: lipid binding
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

StructureStructure

2OBD is a 1 chain structure of sequence from Homo Sapiens. Full crystallographic information is available from OCA Overview of the structure CETP is a 476 amino acid residues protein which has an elongated “boomerang shape” with dimensions of 135 Å X 30 Å X 35 Å. She has a molecular mass of 74 kDa. CETP is a highly hydrophobic and glycosylated protein. In fact 28% of her mass is attributed to N-glycosylated residues : . CETP is constitued of four structural units: At each end of the protein there is a barrel, which is constitued of a highly twisted ß-sheet and two helices called A and B at the and A', B' at C-terminal extremity. Helices B and B' are longer than helices A and A'. Between the two barrels there is a central which is constitued of six antiparallel strands. At the extremity there is a distorted amphiphathic helix called which is an extension of C-teminal extremity interacting with N-terminal residues. Four lipid binding sites CETP's structure reveals a 60 Å long hydrophobic tunnel which traverses the core of the molecule and contains four lipid binding sites: two neutral lipids binding sites and two phospholipids binding sites (one at each end). The center of the tunnel which is called the “neck” is 10 Å wide and 5 Å high that is large enough to permit the passage of neutral lipids. Mutations affecting the neck block the transfer of neutral lipids. The N-opening of the tunnel is 10 Å wide and 5 Å high whereas the C-opening is 13 Å X 5 Å. The C-opening is a little bit larger but both are large enough to allow lipid access. Each opening of the tunnel is plugged by one phospholipid: a phosphatidylcholine, which buries its hydrophobic acyl chain inside the tunnel and its hydrophilic head groups to the solvent. In the middle of the tunnel there is two cholesteryl esters. Cholesteryl ester 1 (CE1) is situated between the N barrel and the central β-sheet. This binding site is mostly constitued of hydrophobic residues and only a few polar. CE1 is not able to establish a hydrogen bond because the Ser 230 is too far away from CE1. However CE1 can establish some π-starking interaction with the His232. Cholesteryl ester 2 (CE2) is situated between the central β-sheet and the C-barrel. CE2 penetrates deeper into the barrel than CE1. This site contains even fewer polar groups than CE1 binding site. That's why CE2 is not able to make any hydrogen-bonding or π-starking interaction. Mobile structures: Helix X and Ω flaps Some mobile structures located near tunnel openings can facilitate the lipid transfer. The amphiphathic which belongs to the C-terminal domain is flexible thanks to her groupment. The hydrophobic face of helix X interacts with phosphatidylcholine 1 located at the N-terminal in order to form an apolar path allowing the access of neutral lipids to the tunnel. Mutations on the hydrophobic face of helix X reduce transfer activities whereas mutations on the polar side do not have any effects on transfer activities. These results prove that helix X plays an important role in transferring neutral lipid between lipoproteins. Near the C-opening, there are also two Ω flaps: Ω1 and Ω2. These flaps are linked through a starking interaction between the Phe292 and Ph350. The flap Ω1 interacts with the oleoyl tail of the cholesteryl ester 2 in order to protect the lipid from aqueous solvent exposure and also to help the exchange of lipids through the C opening.

spinqualitylabelsall models Structure of cholesteryl ester tranfer protein(PDB entry 2obd) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Mechanism allowing neutral-lipid and phospholipid transferMechanism allowing neutral-lipid and phospholipid transfer

In the plasma circulation, CETP often binds high density lipoproteins (HDL) and engages the tranfer of neutral lipids, such as cholesteryl ester and triglyceride among lipoprotein particles. The concave structure of CETP is the only surface able to bind a lipoprotein. Other surfaces of CETP are not able to bind them. It indicates that CETP can bind only one lipoprotein at a time. It means that CETP operates as carrier: CETP accepts neutral lipids from a donor particule and releases them to an acceptor particule.

Binding to a HDL particle, which is cholesteryl ester rich, allows CETP to fill with cholesteryl esters, because one or two cholesteryl esters can enter the tunnel and an equal amount of triglyceride is deposited into HDL. Then the tunnel is refilled with two phospholipid (one at each end) that permits the protein to dissociate from HDL and to retunr to the acqueous phase. CETP also adopts a structural change by twisting its barrel around the central β-sheet in order to bind VLDL particules which are larger than HDL particules. Binding to a VLDL particle, which is triglyceride rich, permits the release of the bound phospholipid. That allows one or two triglycerides to enter the tunnel and an equal amount of cholesteryl ester can be deposit into VLDL. The triglyceride-bound dissociates from VLDL. It carries two phospholipids from the surface of VLDL and travels through the acqueous plasma in order to rebind a HDL particle. Binding to a HDL particle, permits the release of the bound phospholipid and the cycle can continue.

CETP inhibitionCETP inhibition

LDL particles are constitued of a single apolipoprotein which is apo-B100. They are often called “bad cholesterol” because a high rate of LDL leads to a deposition of cholesterol as plaques on artery walls and that can causes cardiovascular problems. Unlike to LDL, HDL particles are considered as “good cholesterol” because they are able to remove cholesterol, via the plasma, from peripheral tissues to the liver, where it will be degraded. They are constitued of apolipoproteins A-I and apo A-II. In fact, a high level of HDL can prevent from the accumulation of cholesterol in the plasma and avoid the developpement of cardiovascular diseases and atherosclerosis. That's why a promising solution to increase the level of HDL is the inhition of CETP.

Natural inhibitorsNatural inhibitors

In the human plasma some natural inhibitors of CETP can be found: like Apo-CI, which his main role is to inhibit CETP, probably by altering the elecric charge of HDL.

Pharmaceutical inhibitorsPharmaceutical inhibitors

The pharmaceutical industry tries to develop inhibitors of CETP in order to decrease the risk of cardivascular diseases. The goal of these inhibitors is to increase the concentration of HDL and decrease the concentration of LDL by blocking cholesteryl esters and triglyceride tranfer. Several inhibitors were found. The first was Torcetrapib followed by Anacetrapib, Dalcetrapib and the last one is Evacetrapib. Torcetrapib succeeds in increasing the level of HDL, but his action has some side effects such as increasingthe blood pressure and the concentration of sodium, bicarbonate and aldosterone. That causes the death of many persons at the stage-III of the clinical trial. That's why this inhibitor was abort. Unlike to torcetrapib, the other do not present any side effect, but they still are in clinical trial. Evacetrapib seems to give the more promising results.

External ressourcesExternal ressources

• Protein Data Bank file on 2OBD

Proteopedia Page Contributors and EditorsProteopedia Page Contributors and Editors

BLEU Mélusine, GOEPFERT Laetitia