Cavities of α1‐antitrypsin that play structural and functional roles
Cavities of α1‐antitrypsin that play structural and functional roles
复制标题
发挥结构和功能作用的α1-抗胰蛋白酶空腔
作者：
Cheolju Lee;J. Maeng;J. Kocher;Byungkook Lee;Myeong
抑制丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）的天然形式是紧张的，这是其抑制活性的关键。先前关于α1‐抗胰蛋白酶（蛇形蛋白酶的原型）稳定突变的研究表明，空腔为该分子的天然菌株提供了结构基础。我们系统地绘制了α1 -抗胰蛋白酶的空腔，通过在空腔壁的残基上设计空腔填充突变来发挥这种结构和功能作用。结果表明，α1 -抗胰蛋白酶分子中存在能量不利的空腔，空腔填充突变稳定了10个靶位点中8个的天然构象。α - 1抗胰蛋白酶的空腔填充突变的稳定效果各不相同（每增加一个亚甲基的稳定性为0.2-1.9 kcal/mol），并且似乎主要取决于空腔环境的结构灵活性。降低α - 1 -抗胰蛋白酶抑制活性的空腔填充突变定位于与反应中心环远端的β - sheet A相互作用的环区。当α1‐抗胰蛋白酶与靶蛋白酶形成复合物时，β‐sheet A及其周围的结构就会被动员。
The native form of inhibitory serine protease inhibitors (serpins) is strained, which is critical for their inhibitory activity. Previous studies on stabilizing mutations of α1‐antitrypsin, a prototype of serpins, indicated that cavities provide a structural basis for the native strain of the molecule. We have systematically mapped the cavities of α1‐antitrypsin that play such structural and functional roles by designing cavity‐filling mutations at residues that line the walls of the cavities. Results show that energetically unfavorable cavities are distributed throughout the α1‐antitrypsin molecule, and the cavity‐filling mutations stabilized the native conformation at 8 out of 10 target sites. The stabilization effect of the individual cavity‐filling mutations of α1‐antitrypsin varied (0.2–1.9 kcal/mol for each additional methylene group) and appeared to depend largely on the structural flexibility of the cavity environment. Cavity‐filling mutations that decreased inhibitory activity of α1‐antitrypsin were localized in the loop regions that interact with β‐sheet A distal from the reactive center loop. The results are consistent with the notion that β‐sheet A and the structure around it mobilize when α1‐antitrypsin forms a complex with a target protease.
影响因子：
56.9
作者：
ERIKSSON, AE;BAASE, WA;MATTHEWS, BW
通讯作者：
MATTHEWS, BW