Structures of Human Golgi-resident Glutaminyl Cyclase and Its Complexes with Inhibitors Reveal a Large Loop Movement upon Inhibitor Binding
Structures of Human Golgi-resident Glutaminyl Cyclase and Its Complexes with Inhibitors Reveal a Large Loop Movement upon Inhibitor Binding
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DOI：
10.1074/jbc.m110.208595
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发表时间：
2011-04-08
影响因子：
4.8
通讯作者：
Wang, Andrew H. -J.
中科院分区：
文献类型：
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作者：
Huang, Kai-Fa;Liaw, Su-Sen;Wang, Andrew H. -J.
在某些肽和蛋白质的N末端，由β-氨基环化酶（QC）催化的异常焦谷氨酸形成与一些病理状况（例如阿尔茨海默病）相关。最近，一种新的β-氨基环化酶（QC）抑制剂PBD 150被证明能够减少焦谷氨酸修饰的淀粉样β肽在阿尔茨海默病转基因小鼠模型脑中的沉积，导致这些转基因动物的学习和记忆的显著改善。在这里，我们报告的1.05-1.40埃的分辨率结构，解决了硫单波长异常色散定相方法，高尔基体管腔催化域的最近确定的高尔基体居民QC（gQC）及其复杂的PBD 150。我们还描述了分泌型QC（sQC）-PBD 150复合物和其他两种gQC-抑制剂复合物的高分辨率结构。gQC结构具有与sQC类似的支架，但具有相对更宽且带负电荷的活性位点，表明与sQC不同的底物特异性。在与PBD 150结合后，gQC中的大环运动允许抑制剂主要通过疏水相互作用紧紧地保持在其活性位点。对结合结构的进一步比较揭示了抑制剂与gQC和sQC的不同相互作用，这与本文报道的抑制剂测定结果一致。由于gQC和sQC可能在体内发挥不同的生物学作用，不同的抑制剂结合模式允许针对gQC和sQC设计特异性抑制剂。
Aberrant pyroglutamate formation at the N terminus of certain peptides and proteins, catalyzed by glutaminyl cyclases (QCs), is linked to some pathological conditions, such as Alzheimer disease. Recently, a glutaminyl cyclase (QC) inhibitor, PBD150, was shown to be able to reduce the deposition of pyroglutamate-modified amyloid-beta peptides in brain of transgenic mouse models of Alzheimer disease, leading to a significant improvement of learning and memory in those transgenic animals. Here, we report the 1.05-1.40 angstrom resolution structures, solved by the sulfur single-wavelength anomalous dispersion phasing method, of the Golgi-luminal catalytic domain of the recently identified Golgi-resident QC (gQC) and its complex with PBD150. We also describe the high-resolution structures of secretory QC (sQC)-PBD150 complex and two other gQC-inhibitor complexes. gQC structure has a scaffold similar to that of sQC but with a relatively wider and negatively charged active site, suggesting a distinct substrate specificity from sQC. Upon binding to PBD150, a large loop movement in gQC allows the inhibitor to be tightly held in its active site primarily by hydrophobic interactions. Further comparisons of the inhibitor-bound structures revealed distinct interactions of the inhibitors with gQC and sQC, which are consistent with the results from our inhibitor assays reported here. Because gQC and sQC may play different biological roles in vivo, the different inhibitor binding modes allow the design of specific inhibitors toward gQC and sQC.