2r4f

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[[Image:2r4f.jpg|left|200px]]
 
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==Substituted Pyrazoles as Hepatselective HMG-COA reductase inhibitors==
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The line below this paragraph, containing "STRUCTURE_2r4f", creates the "Structure Box" on the page.
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<StructureSection load='2r4f' size='340' side='right'caption='[[2r4f]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2r4f]] is a 4 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=2R4F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2R4F FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RIE:(3R,5R)-7-[1-(4-FLUOROPHENYL)-4-(1-METHYLETHYL)-3-{METHYL[(1R)-1-PHENYLETHYL]CARBAMOYL}-1H-PYRAZOL-5-YL]-3,5-DIHYDROXYHEPTANOIC+ACID'>RIE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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{{STRUCTURE_2r4f| PDB=2r4f | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2r4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2r4f OCA], [https://pdbe.org/2r4f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2r4f RCSB], [https://www.ebi.ac.uk/pdbsum/2r4f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2r4f ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/HMDH_HUMAN HMDH_HUMAN] Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/r4/2r4f_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2r4f ConSurf].
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<div style="clear:both"></div>
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'''Substituted Pyrazoles as Hepatselective HMG-COA reductase inhibitors'''
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==See Also==
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*[[HMG-CoA Reductase 3D structures|HMG-CoA Reductase 3D structures]]
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__TOC__
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==Overview==
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</StructureSection>
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In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
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==Disease==
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Known disease associated with this structure: Statins, attenuated cholesterol lowering by OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142910 142910]]
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==About this Structure==
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2R4F is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2R4F OCA].
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==Reference==
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Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H -pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia., Pfefferkorn JA, Choi C, Larsen SD, Auerbach B, Hutchings R, Park W, Askew V, Dillon L, Hanselman JC, Lin Z, Lu GH, Robertson A, Sekerke C, Harris MS, Pavlovsky A, Bainbridge G, Caspers N, Kowala M, Tait BD, J Med Chem. 2008 Jan 10;51(1):31-45. Epub 2007 Dec 12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18072721 18072721]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Finzel, B C.]]
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[[Category: Finzel BC]]
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[[Category: Harris, M S.]]
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[[Category: Harris MS]]
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[[Category: Pavlovsky, A.]]
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[[Category: Pavlovsky A]]
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[[Category: Pfefferkorn, J A.]]
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[[Category: Pfefferkorn JA]]
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[[Category: Alternative splicing]]
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[[Category: Biocynthesis]]
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[[Category: Cholesterol]]
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[[Category: Cholesterol biosynthesis]]
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[[Category: Endoplasmic reticulum]]
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[[Category: Glycoprotein]]
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[[Category: Hmg-coa]]
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[[Category: Lipid synthesis]]
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[[Category: Membrane]]
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[[Category: Nadph]]
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[[Category: Oxidoreductase]]
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[[Category: Peroxisome]]
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[[Category: Polymorphism]]
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[[Category: Statin]]
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[[Category: Steroid biosynthesis]]
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[[Category: Sterol biosynthesis]]
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[[Category: Transmembrane]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:22:16 2008''
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Current revision

Substituted Pyrazoles as Hepatselective HMG-COA reductase inhibitors

PDB ID 2r4f

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