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| | ==Crystal structure of cholestryl esters transfer protein in complex with inhibitors== | | ==Crystal structure of cholestryl esters transfer protein in complex with inhibitors== |
| - | <StructureSection load='4f2a' size='340' side='right' caption='[[4f2a]], [[Resolution|resolution]] 3.11Å' scene=''> | + | <StructureSection load='4f2a' size='340' side='right'caption='[[4f2a]], [[Resolution|resolution]] 3.11Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4f2a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F2A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F2A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4f2a]] 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=4F2A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F2A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0SF:(2R)-3-{[4-(4-CHLORO-3-ETHYLPHENOXY)PYRIMIDIN-2-YL][3-(1,1,2,2-TETRAFLUOROETHOXY)BENZYL]AMINO}-1,1,1-TRIFLUOROPROPAN-2-OL'>0SF</scene>, <scene name='pdbligand=2OB:CHOLESTERYL+OLEATE'>2OB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.11Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ews|4ews]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0SF:(2R)-3-{[4-(4-CHLORO-3-ETHYLPHENOXY)PYRIMIDIN-2-YL][3-(1,1,2,2-TETRAFLUOROETHOXY)BENZYL]AMINO}-1,1,1-TRIFLUOROPROPAN-2-OL'>0SF</scene>, <scene name='pdbligand=2OB:CHOLESTERYL+OLEATE'>2OB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CETP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4f2a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f2a OCA], [https://pdbe.org/4f2a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f2a RCSB], [https://www.ebi.ac.uk/pdbsum/4f2a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f2a ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4f2a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f2a OCA], [http://pdbe.org/4f2a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f2a RCSB], [http://www.ebi.ac.uk/pdbsum/4f2a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f2a ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CETP_HUMAN CETP_HUMAN]] Defects in CETP are the cause of hyperalphalipoproteinemia type 1 (HALP1) [MIM:[http://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> | + | [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 == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CETP_HUMAN CETP_HUMAN]] Involved in the transfer of insoluble cholesteryl esters in the reverse transport of cholesterol. | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Liu, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Qiu, X]] | + | [[Category: Liu S]] |
| - | [[Category: Cholestryl ester transfer protein]] | + | [[Category: Qiu X]] |
| - | [[Category: Cholestryl ester transfer protein-inhibitor complex]]
| + | |
| - | [[Category: High-density lipoprotein]]
| + | |
| - | [[Category: Lipid transport-inhibitor complex]]
| + | |
| - | [[Category: Low-density lipoprotein]]
| + | |
| Structural highlights
4f2a is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 3.11Å |
| Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
CETP_HUMAN Defects in CETP are the cause of hyperalphalipoproteinemia type 1 (HALP1) [MIM:143470. Affected individuals show high levels of alpha-lipoprotein (high density lipoprotein/HDL).[1] [2] [3]
Function
CETP_HUMAN Involved in the transfer of insoluble cholesteryl esters in the reverse transport of cholesterol.
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[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, Maruhama Y, Mabuchi H, Tall AR. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990 Nov 1;323(18):1234-8. PMID:2215607 doi:http://dx.doi.org/10.1056/NEJM199011013231803
- ↑ Takahashi K, Jiang XC, Sakai N, Yamashita S, Hirano K, Bujo H, Yamazaki H, Kusunoki J, Miura T, Kussie P, et al.. A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins. J Clin Invest. 1993 Oct;92(4):2060-4. PMID:8408659 doi:http://dx.doi.org/10.1172/JCI116802
- ↑ Nagano M, Yamashita S, Hirano K, Ito M, Maruyama T, Ishihara M, Sagehashi Y, Oka T, Kujiraoka T, Hattori H, Nakajima N, Egashira T, Kondo M, Sakai N, Matsuzawa Y. Two novel missense mutations in the CETP gene in Japanese hyperalphalipoproteinemic subjects: high-throughput assay by Invader assay. J Lipid Res. 2002 Jul;43(7):1011-8. PMID:12091484
- ↑ Liu S, Mistry A, Reynolds JM, Lloyd DB, Griffor MC, Perry DA, Ruggeri RB, Clark RW, Qiu X. Crystal structures of cholesteryl ester transfer protein in complex with inhibitors. J Biol Chem. 2012 Sep 7. PMID:22961980 doi:http://dx.doi.org/10.1074/jbc.M112.380063
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