3cda
From Proteopedia
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==Thermodynamic and structure guided design of statin hmg-coa reductase inhibitors== | ==Thermodynamic and structure guided design of statin hmg-coa reductase inhibitors== | ||
| - | <StructureSection load='3cda' size='340' side='right' caption='[[3cda]], [[Resolution|resolution]] 2.07Å' scene=''> | + | <StructureSection load='3cda' size='340' side='right'caption='[[3cda]], [[Resolution|resolution]] 2.07Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[3cda]] is a 4 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[3cda]] 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=3CDA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CDA FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.07Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8HI:(3R,5R)-7-{3-(4-FLUOROPHENYL)-1-(1-METHYLETHYL)-4-PHENYL-5-[(4-SULFAMOYLPHENYL)CARBAMOYL]-1H-PYRROL-2-YL}-3,5-DIHYDROXYHEPTANOIC+ACID'>8HI</scene></td></tr> | |
| - | <tr id=' | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3cda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cda OCA], [https://pdbe.org/3cda PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cda RCSB], [https://www.ebi.ac.uk/pdbsum/3cda PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cda ProSAT]</span></td></tr> |
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | |
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [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 == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cd/3cda_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cd/3cda_consurf.spt"</scriptWhenChecked> |
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
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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=3cda ConSurf]. | </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=3cda ConSurf]. | ||
<div style="clear:both"></div> | <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 (>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. | ||
| - | + | ==See Also== | |
| - | + | *[[HMG-CoA Reductase 3D structures|HMG-CoA Reductase 3D structures]] | |
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Finzel BC]] |
| - | [[Category: | + | [[Category: Harris MS]] |
| - | [[Category: | + | [[Category: Pavlovsky A]] |
| - | [[Category: | + | [[Category: Sarver RW]] |
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Current revision
Thermodynamic and structure guided design of statin hmg-coa reductase inhibitors
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