Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.
Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.
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DOI：
10.1021/jp100668y
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发表时间：
2010-04-29
影响因子：
3.3
通讯作者：
Zhan, Chang-Guo
中科院分区：
文献类型：
--
作者：
Hamza, Adel;Tong, Min;AbdulHameed, Mohamed Diwan M.;Liu, Junjun;Goren, Alan C.;Tai, Hsin-Hsiung;Zhan, Chang-Guo
微粒体前列腺素E合成酶-1(mPGES-1)是一种与多种疾病相关的重要酶，是设计新一代抗炎药物的最有前途的靶点。为了建立坚实的结构基础，我们最近利用微粒体谷胱甘肽转移酶-1(MGST1)和Ba3-细胞色素c氧化酶的现有晶体结构作为模板，建立了mPGES-1三聚体结构模型。在本研究中，mPGES-1三聚体模型被用于研究mPGES-1三聚体与底物PGH2和辅因子GSH的详细结合。计算丙氨酸扫描的结果揭示了蛋白质-配体相互作用界面上每个残基对结合亲和力的贡献，相应的湿实验数据支持了计算预测。我们还将我们的mPGES-1三聚体模型与其他现有的三维模型进行了比较，包括替代同源模型和低分辨率晶体结构，发现我们基于MGST1和Ba3-细胞色素c氧化酶的晶体结构的mPGES-1三聚体模型比单纯以MGST1三聚体的低分辨率晶体结构为模板构建的另一种mPGES-1三聚体的同源模型更合理。现有的mPGES-1三聚体的低分辨晶体结构代表了酶的封闭构象，因此不适合于研究mPGES-1与配体的结合。我们的mPGES-1三聚体模型代表了酶的合理开放构象，因此，在未来针对mPGES-1的基于结构的药物设计中，很有希望研究mPGES-1与配体的结合。
Microsomal prostaglandin E synthase-1 (mPGES-1) is an essential enzyme involved in a variety of diseases and is the most promising target for the design of next-generation anti-inflammatory drugs. In order to establish a solid structural base, we recently developed a model of mPGES-1 trimer structure by using available crystal structures of both microsomal glutathione transferase-1 (MGST1) and ba3-cytochrome c oxidase as templates. The mPGES-1 trimer model has been used, in the present study, to examine the detailed binding of mPGES-1 trimer with substrate PGH2 and cofactor GSH. Results obtained from the computational alanine scanning reveal the contribution of each residue at the protein-ligand interaction interface to the binding affinity, and the computational predictions are supported by the data obtained from the corresponding wet experimental tests. We have also compared our mPGES-1 trimer model with other available 3D models, including an alternative homology model and a low-resolution crystal structure, and found that our mPGES-1 trimer model based on the crystal structures of both MGST1 and ba3-cytochrome c oxidase is more reasonable than the other homology model of mPGES-1 trimer constructed by simply using a low-resolution crystal structure of MGST1 trimer alone as a template. The available low-resolution crystal structure of mPGES-1 trimer represents a closed conformation of the enzyme and, thus, is not suitable for studying mPGES-1 binding with ligands. Our mPGES-1 trimer model represents a reasonable open conformation of the enzyme and is, therefore, promising for studying mPGES-1 binding with ligands in future structure-based drug design targeting mPGES-1.
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影响因子：
8
作者：
GUENOT, J;KOLLMAN, PA
通讯作者：
KOLLMAN, PA
影响因子：
7.3
作者：
Kuhn, B;Gerber, P;Stahl, M
通讯作者：
Stahl, M
影响因子：
4.4
作者：
Claveau, D;Sirinyan, M;Mancini, JA
通讯作者：
Mancini, JA
影响因子：
7.3
作者：
Kuhn, B;Kollman, PA
通讯作者：
Kollman, PA
DOI：
10.1073/pnas.96.13.7220
发表时间：
1999-06-22
影响因子：
11.1
作者：
Jakobsson, PJ;Thorén, S;Samuelsson, B
通讯作者：
Samuelsson, B