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首页> 外文期刊>Biochemistry >Crystal structure of phenylmethanesulfonyl fluoride-treated human chymase at 1.9 A
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Crystal structure of phenylmethanesulfonyl fluoride-treated human chymase at 1.9 A

机译：苯甲磺酰氟处理的人糜酶在1.9 A时的晶体结构

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摘要

The X-ray crystal structure of human chymase has been determined to 1.9 A resolution using molecular replacement methods. This first structure of human chymase is present as the Ser 195 ester of alpha-toluenesulfonic acid. The refined structure (Rcryst = 0.183) shows that the inhibitor phenyl moiety lies at the top of the major specificity pocket, S1, while the sulfur is covalently linked to Ser 195-O gamma. The sulfonyl oxygens interact with the oxyanion hole and with His 57-N delta 1. The presence of the inhibitor disturbs the usual gauche position of His 57 and forces it to the trans conformer. Though the primary binding pockets are similarly specific in chymase and chymotrypsin, examination of the extended substrate binding sites reveals the structural basis for chymase's greater discrimination in choosing substrates. The larger 30s loop and its proximity to the active site indicates that it contacts substrate residues C-terminal to the scissile bond. Modeling of substrate at the chymase active site suggests that binding energy may be gained by three main-chain hydrogen bonds provided by substrate residues P2' and P4' and that discriminating interactions with substrate side chains are also likely. The presence of Lys 40 in S1' of human chymase explains its preference for Asp/Glu at P1'. Moreover, the cationic nature of S1' provides a structural basis for human chymase's poor catalytic efficiency when angiotensin II is the substrate.
机译：已经使用分子置换方法将人糜酶的X射线晶体结构确定为1.9 A分辨率。人糜酶的第一结构以α-甲苯磺酸的Ser 195酯存在。精炼的结构（Rcryst = 0.183）表明抑制剂苯基部分位于主要特异性口袋S1的顶部，而硫与Ser 195-Oγ共价连接。磺酰氧与氧阴离子孔和His 57-Nδ1相互作用。抑制剂的存在会干扰His 57的通常纱网位置，并迫使其进入反式构象异构体。尽管主要的结合口袋在糜酶和胰凝乳蛋白酶中具有相似的特异性，但对延长的底物结合位点的检查揭示了糜酶在选择底物时具有更大区分度的结构基础。较大的30s环及其与活性位点的接近程度表明它与易裂键C端的底物残基接触。在糜酶活性位点上对底物进行建模表明，可以通过底物残基P2'和P4'提供的三个主链氢键获得结合能，并且还可能区分与底物侧链的相互作用。人糜酶S1'中Lys 40的存在解释了其对P1'中Asp / Glu的偏好。此外，当血管紧张素II为底物时，S1'的阳离子性质为人糜酶的不良催化效率提供了结构基础。

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