3cd0: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3cd0]] 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=3CD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CD0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3cd0]] 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=3CD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CD0 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6HI:(3R,5R)-7-{2-[(4-FLUOROBENZYL)CARBAMOYL]-4-(4-FLUOROPHENYL)-1-(1-METHYLETHYL)-1H-IMIDAZOL-5-YL}-3,5-DIHYDROXYHEPTANOIC+ACID'>6HI</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]] 2.4&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3cct|3cct]], [[3ccw|3ccw]], [[3ccz|3ccz]], [[3cd5|3cd5]], [[3cd7|3cd7]], [[3cda|3cda]], [[3cdb|3cdb]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6HI:(3R,5R)-7-{2-[(4-FLUOROBENZYL)CARBAMOYL]-4-(4-FLUOROPHENYL)-1-(1-METHYLETHYL)-1H-IMIDAZOL-5-YL}-3,5-DIHYDROXYHEPTANOIC+ACID'>6HI</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HMGCR ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_reductase_(NADPH) Hydroxymethylglutaryl-CoA reductase (NADPH)], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3cd0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cd0 OCA], [https://pdbe.org/3cd0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cd0 RCSB], [https://www.ebi.ac.uk/pdbsum/3cd0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cd0 ProSAT]</span></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=3cd0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cd0 OCA], [https://pdbe.org/3cd0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cd0 RCSB], [https://www.ebi.ac.uk/pdbsum/3cd0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cd0 ProSAT]</span></td></tr>
</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.  
[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]]
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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=3cd0 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=3cd0 ConSurf].
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<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>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3cd0" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[HMG-CoA Reductase 3D structures|HMG-CoA Reductase 3D structures]]
*[[HMG-CoA Reductase 3D structures|HMG-CoA Reductase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Finzel, B C]]
[[Category: Finzel BC]]
[[Category: Harris, M S]]
[[Category: Harris MS]]
[[Category: Pavlovsky, A]]
[[Category: Pavlovsky A]]
[[Category: Sarver, R W]]
[[Category: Sarver RW]]
[[Category: Alternative splicing]]
[[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]]

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