Structural mechanism for statin inhibition of HMG-CoA reductase
Structural mechanism for statin inhibition of HMG-CoA reductase
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DOI：
10.1126/science.1059344
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发表时间：
2001-05-11
期刊：
影响因子：
56.9
通讯作者：
Deisenhofer, J
中科院分区：
文献类型：
--
作者：
Istvan, ES;Deisenhofer, J
HMG-CoA(3-羟基-3-甲基戊二酰辅酶A)还原酶(HMGR)催化胆固醇生物合成的关键步骤。他汀类药物是一种抑制常数值在纳摩尔范围内的HMGR抑制剂，可有效降低血清胆固醇水平，被广泛用于治疗高胆固醇血症。我们测定了人HMGR与六种不同的他汀类药物络合的催化部分的结构。他汀类药物占据了HMG-CoA结合部位的一部分，从而阻止了该底物对活性部位的访问。在HMGR的羧基末端附近，酶-他汀类化合物中的几个催化相关残基无序。如果这些残基不灵活，它们将在空间上阻碍他汀类药物的结合。
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.