Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.
Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.
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抑制剂和底物对接位点之间的结构相互作用有助于深入了解人类 PS1 复合物的机制。
DOI：
10.1016/j.str.2013.09.018
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发表时间：
2014-01-07
期刊：
影响因子：
5.7
通讯作者：
St George-Hyslop, Peter H.
中科院分区：
文献类型：
--
作者：
Li, Yi;Lu, Stephen Hsueh-Jeng;Tsai, Ching-Ju;Bohm, Christopher;Qamar, Seema;Dodd, Roger B.;Meadows, William;Jeon, Amy;McLeod, Adam;Chen, Fusheng;Arimon, Muriel;Berezovska, Oksana;Hyman, Bradley T.;Tomita, Taisuke;Iwatsubo, Takeshi;Johnson, Christopher M.;Farrer, Lindsay A.;Schmitt-Ulms, Gerold;Fraser, Paul E.;St George-Hyslop, Peter H.
早老素介导的跨膜蛋白的内蛋白水解在生理信号传导以及阿尔茨海默病和一些癌症的发病机制中起关键作用。通过文库筛选已经发现了许多抑制剂，但它们的结构机制仍然未知。我们使用了几种生物物理技术来研究人早老素复合物的结构和拟肽γ-分泌酶抑制剂的作用。复合体是双叶的。头部含有nicastrin胞外域。膜包埋的基底具有中央通道和侧向裂缝，其可代表初始底物对接位点。抑制剂结合诱导广泛的结构变化，包括头部的旋转和侧裂的闭合。这些变化阻止底物进入催化口袋并抑制酶。有趣的是，肽底物对接对抑制剂结合位点具有相互作用。类似的相互位移可能是其他抑制剂和“侧门”机制的基础，通过该机制底物进入催化位点。头部含有nicastrin胞外域，并在基部突出一个溶质可接近的空腔。基部具有中央通道和侧裂（推定的底物对接位点）。抑制剂关闭裂缝和通道并旋转头部，阻断底物进入早老素复合物在生理信号传导和疾病期间介导跨膜蛋白的蛋白水解。Li等人描述了人早老素复合物PS1的结构和通道诱导的结构变化。他们提出，类似的变化可能是底物进入催化位点的基础。
Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the “lateral gate” through which substrates access to the catalytic site. The head contains nicastrin ectodomain and overhangs a solute-accessible cavity in base The base has a central channel and a lateral cleft (putative substrate docking site) Inhibitors close the cleft and channel and rotate the head, blocking substrate access Presenilin complexes mediate proteolysis of transmembrane proteins during physiological signaling and disease. Li et al. describe the architecture of human presenilin complex PS1 and inhibitor-induced structural changes. They propose that similar shifts likely underlie substrate access to the catalytic site.
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影响因子：
5.6
作者：
Osenkowski, Pamela;Li, Hua;Ye, Wenjuan;Li, Dongyang;Aeschbach, Lorene;Fraering, Patrick C.;Wolfe, Michael S.;Selkoe, Dennis J.;Li, Huilin
通讯作者：
Li, Huilin
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.1
作者：
Frank, Joachim
通讯作者：
Frank, Joachim
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
DOI：
10.1073/pnas.022523499
发表时间：
2002-01-22
影响因子：
11.1
作者：
Goutte, C;Tsunozaki, M;Priess, JR
通讯作者：
Priess, JR