Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity.
Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity.
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DOI：
10.1021/ja403523p
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发表时间：
2013-06-19
影响因子：
15
通讯作者：
Bogyo, Matthew
中科院分区：
文献类型：
--
作者：
Morell, Montse;Thinh Nguyen Duc;Willis, Amanda L.;Syed, Salahuddin;Lee, Jiyoun;Deu, Edgar;Deng, Yang;Xiao, Junpeng;Turk, Benjamin E.;Jessen, Jason R.;Weiss, Stephen J.;Bogyo, Matthew
基质金属蛋白酶(MMPs)是一种锌内肽酶，在许多病理生理过程中发挥作用，因此是很有前途的药物靶点。然而，该家族的大小以及缺乏可用于成像或抑制特定MMPs成员的高度选择性的化合物，限制了更好地确定其生物学功能的努力。在这里，我们描述了一种结合小分子探针设计的蛋白质工程策略，以选择性地针对基质金属蛋白酶家族的个别成员。具体地说，我们在所选蛋白酶的活性部位附近引入半胱氨酸残基，这种残基不会改变其整体活性或功能，但允许包含活性电泳体的小分子探针直接进行共价修饰。这种特定的探针和目标蛋白酶之间的工程相互作用提供了一种绝对特异性地成像和抑制修饰的蛋白酶的方法。在这里，我们证明了该方法的可行性两个不同的基质金属蛋白酶，基质金属蛋白酶-12和MT1-基质金属蛋白酶(基质金属蛋白酶-14)。
Matrix metalloproteinases (MMPs) are zinc-endopeptidases that play roles in numerous pathophysiological processes and therefore are promising drug targets. However, the large size of this family and a lack of highly selective compounds that can be used for imaging or inhibition of specific MMPs members has limited efforts to better define their biological function. Here we describe a protein engineering strategy coupled with small molecule probe design to selectively target individual members of the MMP family. Specifically, we introduce a cysteine residue near the active site of a selected protease that does not alter its overall activity or function but allows direct covalent modification by a small molecule probe containing a reactive electrophile. This specific engineered interaction between the probe and the target protease provides a means to both image and inhibit the modified protease with absolute specificity. Here we demonstrate the feasibility of the approach for two distinct MMP proteases, MMP-12 and MT1-MMP (MMP-14).
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影响因子：
3.7
作者：
Shen A;Lupardus PJ;Morell M;Ponder EL;Sadaghiani AM;Garcia KC;Bogyo M
通讯作者：
Bogyo M
影响因子：
3.7
作者：
Coyle, Rebecca C.;Latimer, Andrew;Jessen, Jason R.
通讯作者：
Jessen, Jason R.
影响因子：
4
作者：
Remacle, A;Murphy, G;Roghi, C
通讯作者：
Roghi, C
DOI：
10.1165/ajrcmb.20.6.3483
发表时间：
1999-06-01
影响因子：
6.4
作者：
Gibbs, DF;Warner, RL;Varani, J
通讯作者：
Varani, J
影响因子：
14.8
作者：
Blair, Jimmy A.;Rauh, Daniel;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.