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3cda

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Revision as of 13:16, 7 February 2016

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

Structural highlights

3cda 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.
Ligands:
Related:	3cct, 3ccw, 3ccz, 3cd0, 3cd5, 3cd7, 3cdb
Gene:	HMGCR (Homo sapiens)
Activity:	Hydroxymethylglutaryl-CoA reductase (NADPH), with EC number 1.1.1.34
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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.

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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase. J Med Chem. 2008 Jun 10;. PMID:18540668 doi:10.1021/jm7015057

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3cda"

@@ Line 7: / Line 7: @@
 <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='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=3cda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cda OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3cda RCSB], [http://www.ebi.ac.uk/pdbsum/3cda PDBsum]</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=3cda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cda OCA], [http://pdbe.org/3cda PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3cda RCSB], [http://www.ebi.ac.uk/pdbsum/3cda PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</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/chain_selection.php?pdb_ID=2ata 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="background-color:#fffaf0;">
@@ Line 29: / Line 29: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3cda" style="background-color:#fffaf0;"></div>
 ==See Also==

3cda

From Proteopedia

Revision as of 13:16, 7 February 2016

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

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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