The crystal structure of human α1-tryptase reveals a blocked substrate-binding region
The crystal structure of human α1-tryptase reveals a blocked substrate-binding region
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DOI：
10.1016/s0022-2836(02)00625-3
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发表时间：
2002-08-16
影响因子：
5.6
通讯作者：
Sommerhoff, CP
中科院分区：
文献类型：
--
作者：
Marquardt, U;Zettl, F;Sommerhoff, CP
人肥大细胞类胰蛋白酶是与哮喘有关的类胰蛋白酶丝氨酸蛋白酶的一个亚家族。与β-类胰蛋白酶不同的是，α-类胰蛋白酶在蛋白分解方面明显不活跃。我们已经解决了成熟的人α-类胰蛋白酶的2.2埃晶体结构。它揭示了一种框架状的四聚体结构，令人惊讶的是，这种结构不需要肝素结合来保持稳定性。与Beta2-Tryptase形成鲜明对比的是，Ser214-Gly219片段通常为底物结合提供模板，但在Alpha-Tryptase中打结，从而阻断其非启动亚基。这种迄今未观察到的亚位点扭曲与有效的底物结合和加工不相容。Alpha-Tryptase显然是由于Asp216侧链的排斥和吸引而被困在这种非构象中。然而，蛋白水解酶活性可以通过诱导FIT机制产生。(C)2002爱思唯尔科学有限公司。保留所有权利。
Human mast cell tryptases represent a subfamily of trypsin-like serine proteinases implicated in asthma. Unlike beta-tryptases, alpha-tryptases apparently are proteolytically inactive. We have solved the 2.2 Angstrom crystal structure of mature human alpha1-tryptase. It reveals a frame-like tetrameric architecture that, surprisingly, does not require heparin-binding for stability. In marked contrast to beta2-tryptase, the Ser214-Gly219 segment, which normally provides the template for substrate binding, is kinked in alpha-tryptase, thereby blocking its non-primed subsites. This so far unobserved subsite distortion is incompatible with productive substrate binding and processing. alpha-Tryptase apparently is trapped in this off-conformation by repulsions and attractions of the Asp216 side-chain. However, proteolytic activity could be generated by an induced-fit mechanism. (C) 2002 Elsevier Science Ltd. All rights reserved.