Conformational change in rhomboid protease GlpG induced by inhibitor binding to its S' subsites.
Conformational change in rhomboid protease GlpG induced by inhibitor binding to its S' subsites.
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DOI：
10.1021/bi300368b
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发表时间：
2012-05-08
期刊：
影响因子：
2.9
通讯作者：
Ha Y
中科院分区：
文献类型：
--
作者：
Xue Y;Chowdhury S;Liu X;Akiyama Y;Ellman J;Ha Y
菱形蛋白酶在膜的疏水环境内进行蛋白水解。蛋白酶的构象灵活性是必不可少的酶的机制，但这种灵活性的性质是不完全理解。在这里，我们描述的晶体结构的菱形蛋白酶GlpG在复杂的phosphonofluoridate抑制剂，这是共价键合的催化丝氨酸，并延伸到S'侧的基板结合裂缝。抑制剂结合引起膜蛋白酶的细微但广泛的变化。许多跨膜螺旋倾斜并移位，S2和S5之间的差距略微加宽，使得抑制剂可以在它们之间结合。来自作为帽的环（L5）的Phe-245的侧链旋转并揭开底物结合裂缝与脂质双层的开口。多肽骨架在Phe-245处的同时转向移动帽的其余部分并将催化丝氨酸暴露于水溶液。这项研究，连同早期的晶体学研究较小的抑制剂，提出了一个简单的模型来解释基板结合菱形蛋白酶。
Rhomboid protease conducts proteolysis inside the hydrophobic environment of the membrane. The conformational flexibility of the protease is essential for the enzyme mechanism, but the nature of this flexibility is not completely understood. Here we describe the crystal structure of rhomboid protease GlpG in complex with a phosphonofluoridate inhibitor, which is covalently bonded to the catalytic serine, and extends into the S’ side of the substrate binding cleft. Inhibitor binding causes subtle but extensive changes in the membrane protease. Many transmembrane helices tilt and shift positions, and the gap between S2 and S5 is slightly widened so that the inhibitor can bind between them. The side chain of Phe-245 from a loop (L5) that acts as a cap rotates and uncovers the opening of the substrate binding cleft to the lipid bilayer. A concurrent turn of the polypeptide backbone at Phe-245 moves the rest of the cap and exposes the catalytic serine to aqueous solution. This study, together with earlier crystallographic investigation of smaller inhibitors, suggests a simple model to explain substrate binding to rhomboid protease.
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影响因子：
6.7
作者：
Baker RP;Wijetilaka R;Urban S
通讯作者：
Urban S
DOI：
10.1073/pnas.0609981104
发表时间：
2007-01-16
影响因子：
11.1
作者：
Lemieux, M. Joanne;Fischer, Sarah J.;James, Michael N. G.
通讯作者：
James, Michael N. G.
影响因子：
11.4
作者：
Lemberg, MK;Menendez, J;Freeman, M
通讯作者：
Freeman, M
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1073/pnas.0609773104
发表时间：
2007-01-09
影响因子：
11.1
作者：
Ben-Shem, Adam;Fass, Deborah;Bibi, Eitan
通讯作者：
Bibi, Eitan