Sandbox 55: Difference between revisions
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===Active Site=== | ===Active Site=== | ||
The <scene name='Sandbox_55/Four_active_sites_and_residues/1'>four active sites</scene> of HMG-CoA reductase are located at the interface of the two monomers of a dimer (represented by the ball and stick residues). Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site. | The <scene name='Sandbox_55/Four_active_sites_and_residues/1'>four active sites</scene> of HMG-CoA reductase are located at the interface of the two monomers of a dimer (represented by the ball and stick residues). Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site. | ||
The HMG binding pocket is the site of catalysis for HMG-CoA reductase. Three residues are essential for catalysis, E559, D767, and K691. K691 is positioned only 2.7 angstroms from the HMG O2 carbonyl oxygen, and stabilizes the negative charge of the first intermediate. H866 also stabilizes the thiol group. It is also believed that the closeness of E559 and D767 increases the pKa of E559, which allows it to be a proton donor for the final reduction of mevaldehyde to mevalonate. | The HMG binding pocket is the site of catalysis for HMG-CoA reductase. Three residues are essential for catalysis, E559, D767, and K691. K691 is positioned only 2.7 angstroms from the HMG O2 carbonyl oxygen, and stabilizes the negative charge of the first intermediate. H866 also stabilizes the thiol group. It is also believed that the closeness of E559 and D767 increases the pKa of E559, which allows it to be a proton donor for the final reduction of mevaldehyde to mevalonate. The HMG-CoA is bound by a domain consisting of combination of <scene name='Sandbox_55/Secondary_structure/1'>secondary structures</scene>, a central alpha helix surrounded by a triangular set of walls of beta sheets and alpha helices. | ||
When <scene name='HMG-CoA_Reductase/Statin_ator/7'>atorvastatin,</scene> binds, the cis loop forms polar interactions, Ser 684, Asp 690, Lys 691, Lys 692, as well as hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statin. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMG-CoA reductase and thehydrophobic ring structures of atorvastatin also contribute to binding. These interactions result in a Km for HMG-CoA of 4uM. This allows atorvastatin to outcompete HMG-CoA in binding to HMG-CoA reductase.<ref>Roitelman J, Olender EH, Bar-Nun S, Dunn WA Jr, Simoni RD. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J Cell Biol. 1992 Jun;117(5):959-73.</ref> | When <scene name='HMG-CoA_Reductase/Statin_ator/7'>atorvastatin,</scene> binds, the cis loop forms polar interactions, Ser 684, Asp 690, Lys 691, Lys 692, as well as hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statin. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMG-CoA reductase and thehydrophobic ring structures of atorvastatin also contribute to binding. These interactions result in a Km for HMG-CoA of 4uM. This allows atorvastatin to outcompete HMG-CoA in binding to HMG-CoA reductase.<ref>Roitelman J, Olender EH, Bar-Nun S, Dunn WA Jr, Simoni RD. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J Cell Biol. 1992 Jun;117(5):959-73.</ref> | ||
