3CDB
Thermodynamic and structure guided design of statin hmg-coa reductase inhibitors
Summary for 3CDB
| Entry DOI | 10.2210/pdb3cdb/pdb |
| Related | 3CCT 3CCW 3CCZ 3CD0 3CD5 3CD7 3CDA |
| Descriptor | 3-hydroxy-3-methylglutaryl-coenzyme A reductase, (3R,5R)-7-{3-[(4-carbamoylphenyl)sulfamoyl]-4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-pyrrol-1-yl}-3,5-dihydroxyheptanoic acid (3 entities in total) |
| Functional Keywords | oxidoreductase, cholesterol biosynthesis, hmg-coa, nadph, statin, alternative splicing, endoplasmic reticulum, glycoprotein, lipid synthesis, membrane, peroxisome, polymorphism, steroid biosynthesis, transmembrane |
| Biological source | Homo sapiens (Human) |
| Cellular location | Endoplasmic reticulum membrane; Multi-pass membrane protein: P04035 |
| Total number of polymer chains | 4 |
| Total formula weight | 192541.04 |
| Authors | Pavlovsky, A.,Sarver, R.W.,Harris, M.S.,Finzel, B.C. (deposition date: 2008-02-26, release date: 2008-06-17, Last modification date: 2024-02-21) |
| Primary citation | Sarver, R.W.,Bills, E.,Bolton, G.,Bratton, L.D.,Caspers, N.L.,Dunbar, J.B.,Harris, M.S.,Hutchings, R.H.,Kennedy, R.M.,Larsen, S.D.,Pavlovsky, A.,Pfefferkorn, J.A.,Bainbridge, G. Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme a reductase. J.Med.Chem., 51:3804-3813, 2008 Cited by PubMed Abstract: 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. PubMed: 18540668DOI: 10.1021/jm7015057 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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