HMG-CoA Reductase: Difference between revisions

A number of crystal structures of HMGR with bound statins have been solved which elucidate how the statin molecule is bound by HMGR. Statins in general occupy the active site of HMGR, preventing HMG-CoA from binding. The structure of HMGR with bound statins (<scene name='HMG-CoA_Reductase/Statin_ator/7'>here atorvastatin,</scene> ([[1hwk]]) marketed as [[Lipitor]]) shows that the cis loop forms a number of polar interactions with the statin inhibitor, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of the statins contribute to binding as well.<ref>PMID:11349148</ref> These interactions result in the statins binding to HMGR with a K_i of between .1-2.3nM while the Michaelis constant K_M for HMG-CoA is 4uM, allowing the statins to outcompete HMG-CoA in binding to HMGR.<ref>PMID:7784310</ref> Additional structures of HMGR with the statins <scene name='HMG-CoA_Reductase/Statin_meva/5'>mevastatin (compactin)</scene> ([[1hw8]]), <scene name='HMG-CoA_Reductase/Statin_simva/5'>simvastatin</scene> ([[1hw9]], [[Zocor]], [[Simvastatin]]), <scene name='HMG-CoA_Reductase/Statin_fluva/6'>fluvastatin </scene>([[1hwi]], [[Lescol]], [[Fluvastatin]]), <scene name='HMG-CoA_Reductase/Statin_ceriv/3'>cerivastatin</scene> ([[1hwj]], [[Baycol]]), and <scene name='HMG-CoA_Reductase/Statin_rosu/5'>rosuvastatin</scene> ([[1hwl]], [[Crestor]], [[Rosuvastatin]]) highlight the important residues involved in inhibitor binding. Other statins approved by the FDA include [[Lovastatin]].

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