View source for 4ews


==Crystal structure of cholesteryl ester transfer protein in complex with inhibitors==
<StructureSection load='4ews' size='340' side='right'caption='[[4ews]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ews]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EWS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EWS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.59&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RP:ETHYL+(2R,4S)-4-{[3,5-BIS(TRIFLUOROMETHYL)BENZYL](METHOXYCARBONYL)AMINO}-2-ETHYL-6-(TRIFLUOROMETHYL)-3,4-DIHYDROQUINOLINE-1(2H)-CARBOXYLATE'>0RP</scene>, <scene name='pdbligand=2OB:CHOLESTERYL+OLEATE'>2OB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DLP:1,2-DILINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>DLP</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ews FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ews OCA], [https://pdbe.org/4ews PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ews RCSB], [https://www.ebi.ac.uk/pdbsum/4ews PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ews ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CETP_HUMAN CETP_HUMAN] Defects in CETP are the cause of hyperalphalipoproteinemia type 1 (HALP1) [MIM:[https://omim.org/entry/143470 143470]. Affected individuals show high levels of alpha-lipoprotein (high density lipoprotein/HDL).<ref>PMID:2215607</ref> <ref>PMID:8408659</ref> <ref>PMID:12091484</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CETP_HUMAN CETP_HUMAN] Involved in the transfer of insoluble cholesteryl esters in the reverse transport of cholesterol.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human plasma cholesteryl ester transfer protein (CETP) transports cholesteryl ester from the antiatherogenic high-density lipoproteins (HDL) to the proatherogenic lower density species, such as (very) low-density lipoproteins ((V)LDL). Inhibition of CETP has been shown to raise human plasma HDL cholesterol (HDL-C) levels and is potentially a novel approach for the prevention of cardiovascular diseases (CVD). Here we report the crystal structures of CETP in complex with torcetrapib, a CETP inhibitor that has been tested in Phase 3 clinical trials, and compound 2, an analogue from a structurally distinct inhibitor series. In both crystal structures, the inhibitors are buried deeply within the protein, shifting the bound cholesteryl ester in the N-terminal pocket of the long hydrophobic tunnel and displacing the phospholipid from that pocket. The lipids in the C-terminal pocket of the hydrophobic tunnel remain unchanged. The inhibitors are positioned near the narrowing neck of the hydrophobic tunnel of CETP and thus block the connection between the N- and C-terminal pockets. These structures illuminate the unusual inhibition mechanism of these compounds and support the tunnel mechanism for neutral lipid transfer by CETP. These highly lipophilic inhibitors bind mainly through extensive hydrophobic interactions with the protein and the shifted cholesteryl ester molecule. However, polar residues, such as Ser230 and His232, are also found in the inhibitor binding site. An enhanced understanding of the inhibitor binding site may provide opportunities to design novel CETP inhibitors possessing more drug-like physical properties, distinct modes of action or alternative pharmacological profiles.

Crystal structures of cholesteryl ester transfer protein in complex with inhibitors.,Liu S, Mistry A, Reynolds JM, Lloyd DB, Griffor MC, Perry DA, Ruggeri RB, Clark RW, Qiu X J Biol Chem. 2012 Sep 7. PMID:22961980<ref>PMID:22961980</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ews" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Liu S]]
[[Category: Qiu X]]