Sandbox 215: Difference between revisions
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{{STRUCTURE_2obd| PDB=2obd | SCENE= }} | {{STRUCTURE_2obd| PDB=2obd | SCENE= }} | ||
[http://en.wikipedia.org/wiki/Cholesterylester_transfer_protein Cholesteryl ester transfer protein (CETP)], which is also called plasma lipid transfer protein belongs to a family of proteins that | [http://en.wikipedia.org/wiki/Cholesterylester_transfer_protein Cholesteryl ester transfer protein (CETP)], which is also called plasma lipid transfer protein belongs to a family of proteins that allow lipid transfer. The [http://en.wikipedia.org/wiki/Homo_sapiens human] cholesteryl ester transfer protein is a hydrophobic glycoprotein which is mainly synthesized in the liver, but also in the intestine, spleen and adrenal glands. The gene coding for this protein is located on the sixteen chromosome. | ||
In the plasma, CETP plays an important role in the transport of cholesteryl esters from the atheroprotective high-density lipoproteins (HDL) to the atherogenic lower-density lipoproteins (LDL) and also mediates the transport of triglycerides from LDL to HDL. | In the plasma, CETP plays an important role in the transport of cholesteryl esters from the atheroprotective high-density lipoproteins (HDL) to the atherogenic lower-density lipoproteins (LDL) and also mediates the transport of triglycerides from LDL to HDL. | ||
Most of the time, CETP facilites homoexchange by exchanging a triglyceride for another triglyceride and a cholesteryl ester for a cholesteryl ester between lipoproteins. However, CETP can also | Most of the time, CETP facilites homoexchange by exchanging a triglyceride for another triglyceride and a cholesteryl ester for a cholesteryl ester between lipoproteins. However, CETP can also promote heteroexchange. | ||
The cristal structure of CETP, in complex with four bound lipid molecules at 2, | 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 and each opening is plugged by an amphiphilic phosphatidylcholine. | ||
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In the middle of the tunnel there is two cholesteryl esters binding sites. | In the middle of the tunnel there is two cholesteryl esters binding sites. | ||
*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 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 <scene name='Sandbox_215/Ser230/1'>Ser 230</scene> 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. | *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. | ||
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The amphiphathic <scene name='Sandbox_215/Helix_x/1'>helix X</scene> which belongs to the C-terminal domain is flexible thanks to her | The amphiphathic <scene name='Sandbox_215/Helix_x/1'>helix X</scene> which belongs to the C-terminal domain is flexible thanks to her | ||
<scene name='Sandbox_215/Gly462-phe463-pro464/1'>Gly462-Phe463-Pro464</scene> 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. | <scene name='Sandbox_215/Gly462-phe463-pro464/1'>Gly462-Phe463-Pro464</scene> 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.</StructureSection> | 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.</StructureSection> | ||
== Mechanism allowing neutral-lipid and phospholipid transfer <ref name="rasmol" /> <ref name="rasmol1">James A Hamilton & Richard J Deckelbaum. Crystal structure of CETP: new hopes for raising HDL to decrease risk of cardiovascular disease? Nature Structural & Molecular Biology 14, 95 - 97 (2007). [https://www-ncbi-nlm-nih-gov.scd-rproxy.u-strasbg.fr/pubmed/17277799 PMID: 17277799] [http://www.nature.com.scd-rproxy.u-strasbg.fr/nsmb/journal/v14/n2/full/nsmb0207-95.html doi:10.1038/nsmb0207-95]</ref>== | == Mechanism allowing neutral-lipid and phospholipid transfer <ref name="rasmol" /> <ref name="rasmol1">James A Hamilton & Richard J Deckelbaum. Crystal structure of CETP: new hopes for raising HDL to decrease risk of cardiovascular disease? Nature Structural & Molecular Biology 14, 95 - 97 (2007). [https://www-ncbi-nlm-nih-gov.scd-rproxy.u-strasbg.fr/pubmed/17277799 PMID: 17277799] [http://www.nature.com.scd-rproxy.u-strasbg.fr/nsmb/journal/v14/n2/full/nsmb0207-95.html doi:10.1038/nsmb0207-95]</ref>== | ||
In the plasma | In the plasma, 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 only bind 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 phospholipids (one at each end) that | 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 phospholipids (one at each end) that permit the protein to dissociate from HDL and to return 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 and to permit the release of the bound phospholipid. Then the cycle can continue. | ||
==CETP inhibition <ref name="rasmol1" />== | ==CETP inhibition <ref name="rasmol1" />== | ||
[http://en.wikipedia.org/wiki/LDL 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 | [http://en.wikipedia.org/wiki/LDL 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 deposit of cholesterol as plaques in arteries and that can cause cardiovascular problems. | ||
Unlike to LDL, [http://en.wikipedia.org/wiki/High-density_lipoprotein 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. | Unlike to LDL, [http://en.wikipedia.org/wiki/High-density_lipoprotein 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. | ||
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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 is Torcetrapib followed of Anacetrapib, Dalcetrapib and Evacetrapib. | 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 is Torcetrapib followed of Anacetrapib, Dalcetrapib and Evacetrapib. | ||
Torcetrapib was developed by Pfizer in order to treat hypercholesterolemia (high cholesterol levels) and prevent [http://en.wikipedia.org/wiki/Atherosclerosis atherosclerosis]. Torcetrapib managed to reduce CETP activity and succeeds in increasing the level of HDL. However, in stage-III clinical trials, Torcetrapib causes significant changes in vital signs: like increases the blood pressure, the concentration of sodium, bicarbonate and aldosterone. The explanations for this unexpected result remain unclear | Torcetrapib was developed by Pfizer in order to treat hypercholesterolemia (high cholesterol levels) and prevent [http://en.wikipedia.org/wiki/Atherosclerosis atherosclerosis]. Torcetrapib managed to reduce CETP activity and succeeds in increasing the level of HDL. However, in stage-III clinical trials, Torcetrapib causes significant changes in vital signs: like increases the blood pressure, the concentration of sodium, bicarbonate and aldosterone. The explanations for this unexpected result remain unclear but perhaps increased binding of torcetrapib-CETP complexes to HDL may interfer with the anti-cardiovascular diseases (anti-CVD) activity of HDL causing the death of many persons. That's why, in 2006, this inhibitor was halted. | ||
Unlike to Torcetrapib, the other which still are in clinical trial do not have any side effects. | Unlike to Torcetrapib, the other which still are in clinical trial do not have any side effects. | ||