Sandbox 215: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
|||
| Line 18: | Line 18: | ||
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 : <scene name='Sandbox_215/N-glycosylation/3'>88, 240, 341 and 396</scene>. | 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 : <scene name='Sandbox_215/N-glycosylation/3'>88, 240, 341 and 396</scene>. | ||
CETP is constitued of four structural units: | CETP is constitued of four structural units: <ref>Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF, Griffor MC, Hawrylik SJ, Hayward CM, Hensley P, Hoth LR, Karam GA, Lira ME, Lloyd DB, McGrath KM, Stutzman-Engwall KJ, Subashi AK, Subashi TA, Thompson JF, Wang IK, Zhao H, Seddon AP. Crystal Structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nature Structural & Molecular Biology. 2007 Feb;14(2):106-13. Epub 2007 Jan 21. [http://www.ncbi.nlm.nih.gov/pubmed?term=17237796. PMID: 17237796] [http://www.nature.com.scd-rproxy.u-strasbg.fr/nsmb/journal/v14/n2/full/nsmb1197.html doi:10.1038/nsmb1197]</ref> | ||
* 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 <scene name='Sandbox_215/N-terminal/2'>N-terminal extremity</scene> and A', B' at C-terminal extremity. Helices B and B' are longer than helices A and A'. | * 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 <scene name='Sandbox_215/N-terminal/2'>N-terminal extremity</scene> and A', B' at C-terminal extremity. Helices B and B' are longer than helices A and A'. | ||
| Line 27: | Line 29: | ||
===Four lipid binding sites=== | ===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. | 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. <ref>Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF, Griffor MC, Hawrylik SJ, Hayward CM, Hensley P, Hoth LR, Karam GA, Lira ME, Lloyd DB, McGrath KM, Stutzman-Engwall KJ, Subashi AK, Subashi TA, Thompson JF, Wang IK, Zhao H, Seddon AP. Crystal Structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nature Structural & Molecular Biology. 2007 Feb;14(2):106-13. Epub 2007 Jan 21. [http://www.ncbi.nlm.nih.gov/pubmed?term=17237796. PMID: 17237796] [http://www.nature.com.scd-rproxy.u-strasbg.fr/nsmb/journal/v14/n2/full/nsmb1197.html doi:10.1038/nsmb1197]</ref> | ||
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. | |||
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. | 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. | ||
| Line 52: | Line 56: | ||
[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 deposition of cholesterol as plaques on artery walls and that can causes cardiovascular problems. | [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 deposition of cholesterol as plaques on artery walls and that can causes 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. <ref>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> | ||
===Natural inhibitors=== | ===Natural 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. | 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. <ref>Philip J. Barter, H. Bryan Brewer, Jr, M. John Chapman, Charles H. Hennekens, Daniel J. Rader and Alan R. Tall. Cholesteryl Ester Transfer Protein : A Novel Target for Raising HDL and Inhibiting Atherosclerosis. Arterioscler Thromb Vasc Biol 2003, 23:160-167: originally published online January 2, 2003.[http://atvb.ahajournals.org/content/23/2/160.full doi: 10.1161/01.ATV.0000054658.91146.64].</ref> | ||
===Pharmaceutical inhibitors=== | ===Pharmaceutical inhibitors=== | ||
| Line 62: | Line 68: | ||
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. | 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. | 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. | 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. <ref>Cao G, Beyer TP, Zhang Y, Schmidt RJ, Chen YQ, Cockerham SL, Zimmerman KM, Karathanasis SK, Cannady EA, Fields T, Mantlo NB. Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure. The Journal of Lipid Research, December 2011. [https://www-ncbi-nlm-nih-gov.scd-rproxy.u-strasbg.fr/pubmed/21957197 PMID: 21957197]. [http://www.jlr.org.scd-rproxy.u-strasbg.fr/content/52/12/2169.long doi: 10.1194/jlr.M018069]</ref> | ||
==External ressources== | ==External ressources== | ||
| Line 71: | Line 78: | ||
<references/> | <references/> | ||
== Proteopedia Page Contributors and Editors == | == Proteopedia Page Contributors and Editors == | ||
BLEU Mélusine, GOEPFERT Laetitia | BLEU Mélusine, GOEPFERT Laetitia | ||
