Istvan Eva
Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, Campus Box 8230, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Atheroscler Suppl. 2003 Mar;4(1):3-8. doi: 10.1016/s1567-5688(03)00003-5.
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 1 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.
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射线晶体学研究中，我们已经确定了该酶催化部分与他汀类分子复合物的结构。这些研究表明，他汀类分子的HMG样部分占据了酶的HMG结合位点，他汀类药物的疏水基团占据了酶催化结构域中柔性螺旋移动所暴露的一个结合位点。除了由HMG样部分形成的键外，他汀类药物还根据结构差异表现出不同类型和数量的结合相互作用。1型他汀类药物（如辛伐他汀）通过十氢化萘环结构表现出结合，而2型他汀类药物（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2型他汀类药物所没有的氢键；瑞舒伐他汀通过其带负电的砜基团表现出独特的键。他汀类药物结构和结合特性的差异可能部分导致HMG-CoA还原酶抑制效力和其他药理特性的差异。
