Statin inhibition of HMG-CoA reductase: a 3-dimensional view
Statin inhibition of HMG-CoA reductase: a 3-dimensional view
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DOI：
10.1016/s1567-5688(03)00003-5
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发表时间：
2003-03-01
影响因子：
--
通讯作者：
Istvan, E
中科院分区：
文献类型：
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作者：
Istvan, E
他汀类药物通过抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶来发挥作用，从而减少胆固醇的合成。在X射线结晶学研究中，我们确定了与他汀类分子形成络合物的酶的催化部分的结构。这些研究表明，他汀类分子的HMG部分占据了酶的HMG结合部位，而他汀类分子的疏水基团占据了酶催化区域中柔性螺旋运动暴露的结合部位。除了类HMG部分形成的键外，他汀类药物还表现出不同类型和数量的结合作用，这与结构差异有关。I型他汀类药物(例如辛伐他汀)通过十氢林环结构结合，而2型他汀类药物(例如瑞舒伐他汀、阿托伐他汀、氟伐他汀)通过其氟苯基表现出额外的结合。瑞舒伐他汀和阿托伐他汀表现出其他类型的他汀类药物所没有的氢键；瑞舒伐他汀通过其电负性砜基表现出独特的键。他汀类药物结构和结合特性的不同可能是HMG-CoA还原酶抑制活性和其他药理特性不同的部分原因。(C)2003爱思唯尔爱尔兰科学有限公司。保留所有权利。
Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thereby reducing cholesterol synthesis. In X-ray crystallographic studies, we have determined the structures of the catalytic portions of the enzyme in complex with statin molecules. These studies show that the HMG-like moiety of statin molecules occupy the HMG binding site of the enzyme, with the hydrophobic groups of the statins occupying a binding site exposed by movement of flexible helices in the enzyme catalytic domain. In addition to bonds formed by the HMG-like moiety, statins exhibit different types and numbers of binding interactions in association with structural differences. Type I statins (e.g., simvastatin) exhibit binding via a decalin ring structure, and type 2 statins (e.g., rosuvastatin, atorvastatin, fluvastatin) exhibit additional binding via their fluorophenyl group. Rosuvastatin and atorvastatin exhibit hydrogen bonds absent from other type 2 statins; rosuvastatin exhibits a unique bond via its electronegative sulfone group. Differences in statin structure and binding characteristics may partially contribute to differences in potency of HMG-CoA reductase inhibition and other pharmacologic properties. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.