3cdb: Difference between revisions

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 ==Thermodynamic and structure guided design of statin hmg-coa reductase inhibitors==
-<StructureSection load='3cdb' size='340' side='right' caption='[[3cdb]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='3cdb' size='340' side='right'caption='[[3cdb]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3cdb]] is a 4 chain structure with 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=3CDB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3CDB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3cdb]] 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=3CDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CDB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9HI:(3R,5R)-7-{3-[(4-CARBAMOYLPHENYL)SULFAMOYL]-4,5-BIS(4-FLUOROPHENYL)-2-(1-METHYLETHYL)-1H-PYRROL-1-YL}-3,5-DIHYDROXYHEPTANOIC+ACID'>9HI</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]] 2.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3cct|3cct]], [[3ccw|3ccw]], [[3ccz|3ccz]], [[3cd0|3cd0]], [[3cd5|3cd5]], [[3cd7|3cd7]], [[3cda|3cda]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9HI:(3R,5R)-7-{3-[(4-CARBAMOYLPHENYL)SULFAMOYL]-4,5-BIS(4-FLUOROPHENYL)-2-(1-METHYLETHYL)-1H-PYRROL-1-YL}-3,5-DIHYDROXYHEPTANOIC+ACID'>9HI</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HMGCR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3cdb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cdb OCA], [https://pdbe.org/3cdb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cdb RCSB], [https://www.ebi.ac.uk/pdbsum/3cdb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cdb ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_reductase_(NADPH) Hydroxymethylglutaryl-CoA reductase (NADPH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.34 1.1.1.34] </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=3cdb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cdb OCA], [http://pdbe.org/3cdb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3cdb RCSB], [http://www.ebi.ac.uk/pdbsum/3cdb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3cdb ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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.
+[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.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
    <jmolCheckbox>
-     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cd/3cdb_consurf.spt"</scriptWhenChecked>
+     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cd/3cdb_consurf.spt"</scriptWhenChecked>
      <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
      <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 22: / Line 20: @@
 </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=3cdb ConSurf].
 <div style="clear:both"></div>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (&gt;1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.
-Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase.,Sarver RW, Bills E, Bolton G, Bratton LD, Caspers NL, Dunbar JB, Harris MS, Hutchings RH, Kennedy RM, Larsen SD, Pavlovsky A, Pfefferkorn JA, Bainbridge G J Med Chem. 2008 Jun 10;. PMID:18540668<ref>PMID:18540668</ref>
+==See Also==
+*[[HMG-CoA Reductase 3D structures|HMG-CoA Reductase 3D structures]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 3cdb" style="background-color:#fffaf0;"></div>
-== References ==
-<references/>
 __TOC__
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Finzel, B C]]
+[[Category: Large Structures]]
-[[Category: Harris, M S]]
+[[Category: Finzel BC]]
-[[Category: Pavlovsky, A]]
+[[Category: Harris MS]]
-[[Category: Sarver, R W]]
+[[Category: Pavlovsky A]]
-[[Category: Alternative splicing]]
+[[Category: Sarver RW]]
-[[Category: Cholesterol biosynthesis]]
-[[Category: Endoplasmic reticulum]]
-[[Category: Glycoprotein]]
-[[Category: Hmg-coa]]
-[[Category: Lipid synthesis]]
-[[Category: Membrane]]
-[[Category: Nadph]]
-[[Category: Oxidoreductase]]
-[[Category: Peroxisome]]
-[[Category: Polymorphism]]
-[[Category: Statin]]
-[[Category: Steroid biosynthesis]]
-[[Category: Transmembrane]]