3cd7: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3cd7]] 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=3CD7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CD7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3cd7]] 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=3CD7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CD7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=882:(3R,5R)-7-[5-(ANILINOCARBONYL)-3,4-BIS(4-FLUOROPHENYL)-1-ISOPROPYL-1H-PYRROL-2-YL]-3,5-DIHYDROXYHEPTANOIC+ACID'>882</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]] 2.05&#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]], [[3cd0|3cd0]], [[3cd5|3cd5]], [[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=882:(3R,5R)-7-[5-(ANILINOCARBONYL)-3,4-BIS(4-FLUOROPHENYL)-1-ISOPROPYL-1H-PYRROL-2-YL]-3,5-DIHYDROXYHEPTANOIC+ACID'>882</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=3cd7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cd7 OCA], [https://pdbe.org/3cd7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cd7 RCSB], [https://www.ebi.ac.uk/pdbsum/3cd7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cd7 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=3cd7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cd7 OCA], [https://pdbe.org/3cd7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cd7 RCSB], [https://www.ebi.ac.uk/pdbsum/3cd7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cd7 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=3cd7 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=3cd7 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 (&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 3cd7" 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]]

Latest revision as of 12:34, 21 February 2024

Thermodynamic and structure guided design of statin hmg-coa reductase inhibitorsThermodynamic and structure guided design of statin hmg-coa reductase inhibitors

Structural highlights

3cd7 is a 4 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 2.05Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

3cd7, resolution 2.05Å

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OCA
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