组织蛋白酶b特异性非共价型抑制剂开发的结构基础:组织蛋白酶B-E64c复合物的晶体结构

Atsushi Yamamoto , Koji Tomoo , Ken-ichi Matsugi , Tadaoki Hara , Yasuko In , Mitsuo Murata , Kunihiro Kitamura , Toshimasa Ishida
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引用次数: 31

摘要

为了阐明组织蛋白酶B的Sn亚位(n=1 -3)的底物特异性,用x射线衍射法分析了E64c [(+)-(2S,3S)-3-(1-[n -(3-甲基丁基)氨基]-亮基羰基)氧烷-2-羧酸]对其晶体结构的抑制作用。迭代人工重建和方便的结构共轭精化将R因子和自由R因子分别降低到19.7%和23.9%,其中130个水分子使用10到2.3 Å分辨率的14,759个独立反射进行精化。E64c的环氧羰基碳与cys29s - γ原子共价结合,其余部分位于Sn亚位(n= 1-3)。这些亚位的底物特异性是基于它们与抑制剂的相互作用来表征的。基于这些结构数据,我们开发了一种新的组织蛋白酶b特异性非共价型抑制剂,它可能与S2 ' -S3结合。同时具有CA074和E64c结构元素的分子设计,在能量最小化和分子动力学(MD)模拟的辅助下,可能会得到一种新的铅非共价型抑制剂。
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Structural basis for development of cathepsin B-specific noncovalent-type inhibitor: crystal structure of cathepsin B–E64c complex

In order to elucidate the substrate specificity of the Sn subsites (n=1–3) of cathepsin B, its crystal structure inhibited by E64c [(+)-(2S,3S)-3-(1-[N-(3-methylbutyl)amino]-leucylcarbonyl)oxirane-2-carboxylic acid] was analyzed by the X-ray diffraction method. Iterative manual rebuilding and convenient conjugate refinement of structure decreased R- and free R-factors to 19.7% and to 23.9%, respectively, where 130 water molecules were included for the refinement using 14,759 independent reflections from 10 to 2.3 Å resolution. The epoxy carbonyl carbon of E64c was covalently bonded to the Cys29 Sγ atom and the remaining parts were located at Sn subsites (n=1–3). The substrate specificity of these subsites was characterized based on their interactions with the inhibitor. Base on these structural data, we developed a novel cathepsin B-specific noncovalent-type inhibitor, which may bind to S2′–S3. The molecular design of possessing structural elements of both CA074 and E64c, assisted by energy minimization and molecular dynamics (MD) simulation, may lead to a new lead noncovalent-type inhibitor.

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