Matsumoto K, Mizoue K, Kitamura K, Tse W C, Huber C P, Ishida T
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Biopolymers. 1999;51(1):99-107. doi: 10.1002/(SICI)1097-0282(1999)51:1<99::AID-BIP11>3.0.CO;2-R.
This paper focuses on the inhibitory mechanism of E-64 and its derivatives (epoxysuccinyl-based inhibitors) with some cysteine proteases, based on the binding modes observed in the x-ray crystal structures of their enzyme-inhibitor complexes. E-64 is a potent irreversible inhibitor against general cysteine proteases, and its binding modes with papain, actinidin, cathepsin L, and cathepsin K have been reviewed at the atomic level. E-64 interacts with the Sn subsites of cysteine proteases. Although the Sn-Pn (n = 1-3) interactions of the inhibitor with the main chains of the active site residues are similar in respective complexes, the significant difference is observed in the side-chain interactions of S2-P2 and S3-P3 pairs because of different residues constituting the respective subsites. E-64-c and CA074 are representative derivatives developed from E-64 as a clinical usable and a cathepsin B-specific inhibitors, respectively. In contrast with similar binding/inhibitory modes of E-64-c and E-64 for cysteine proteases, the inhibitory mechanism of cathepsin B-specific CA074 results from the binding to the Sn' subsite.
本文基于在其酶-抑制剂复合物的X射线晶体结构中观察到的结合模式，重点研究了E-64及其衍生物（环氧琥珀酰基抑制剂）对某些半胱氨酸蛋白酶的抑制机制。E-64是一种针对一般半胱氨酸蛋白酶的强效不可逆抑制剂，并且已经在原子水平上综述了它与木瓜蛋白酶、猕猴桃蛋白酶、组织蛋白酶L和组织蛋白酶K的结合模式。E-64与半胱氨酸蛋白酶的Sn亚位点相互作用。尽管在各个复合物中抑制剂与活性位点残基主链的Sn-Pn（n = 1-3）相互作用相似，但由于构成各个亚位点的残基不同，在S2-P2和S3-P3对的侧链相互作用中观察到了显著差异。E-64-c和CA074分别是从E-64开发而来的具有临床可用性的抑制剂和组织蛋白酶B特异性抑制剂的代表性衍生物。与E-64-c和E-64对半胱氨酸蛋白酶的相似结合/抑制模式相反，组织蛋白酶B特异性抑制剂CA074的抑制机制是由于其与Sn'亚位点的结合。
