Effect of the Flexible Regions of the Oncoprotein Mouse Double Minute X on Inhibitor Binding Affinity
文献类型：期刊论文
| 作者 | Chen, Yao1; Huang, Yongqi1; Qin, Lingyun1; Su, Zhengding1; Liu, Huili2; Chen, Rong1; Cheng, Xiyao1; Zhou, Jingjing1 |
| 刊名 | BIOCHEMISTRY
 |
| 出版日期 | 2017-11-07 |
| 卷号 | 56期号:44页码:5943-5954 |
| DOI | 10.1021/acs.biochem.7b00903 |
| 文献子类 | Article |
| 英文摘要 | The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally. In this work, we have investigated how the intrinsic flexible regions of the N-terminal domain of MdmX (N-MdmX) affect the affinity of the Mdm2 inhibitor nutlin-3a using protein engineering. Guided by heteronuclear nuclear Overhauser effect measurements, we identified the flexible regions that affect inhibitor binding affinity around the ligand-binding pocket on N-MdmX. A disulfide engineering mutant, N-MdmX(C25-C110/C76-C88), which incorporated two staples to rigidify the ligand-binding pocket, allowed an affinity for nutlin-3a higher than that of wild-type N-MdmX (K-d similar to 0.48 vs K-d similar to 20.3 mu M). Therefore, this mutant provides not only an effective protein model for screening and designing of MdmX inhibitors but also a valuable clue for enhancing the intermolecular interactions of the pharmacophores of a ligand with pronounced flexible regions. In addition, our results revealed an allosteric ligand-binding mechanism of N-MdmX in which the ligand initially interacts with a compact core, followed by augmenting intermolecular interactions with intrinsic flexible regions. This strategy should also be applicable to many other protein targets to accelerate drug discovery. |
| WOS关键词 | MOLECULAR-DYNAMICS SIMULATIONS ; P53 PATHWAY ; CONFORMATIONAL SELECTION ; MDM2 INHIBITORS ; CANCER-THERAPY ; FREE-ENERGY ; PROTEIN ; MECHANISM ; RETINOBLASTOMA ; INACTIVATION |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000414886900011 |
| 资助机构 | Hubei Provincial Innovative Project(2016ACA128) ; Hubei Provincial Innovative Project(2016ACA128) ; Wuhan Natural Science Foundation(201506101010033) ; Wuhan Natural Science Foundation(201506101010033) ; National Natural Science Foundation of China(21603121 ; National Natural Science Foundation of China(21603121 ; State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics(T152604) ; State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics(T152604) ; 31500132) ; 31500132) ; Hubei Provincial Innovative Project(2016ACA128) ; Hubei Provincial Innovative Project(2016ACA128) ; Wuhan Natural Science Foundation(201506101010033) ; Wuhan Natural Science Foundation(201506101010033) ; National Natural Science Foundation of China(21603121 ; National Natural Science Foundation of China(21603121 ; State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics(T152604) ; State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics(T152604) ; 31500132) ; 31500132) |
| 源URL | [http://ir.wipm.ac.cn/handle/112942/11552]  |
| 专题 | 武汉物理与数学研究所_高技术创新与发展中心 |
| 作者单位 | 1.Hubei Univ Technol, Minist Educ, Inst Biomed & Pharmaceut Sci, Key Lab Ind Fermentat, Wuhan 430068, Hubei, Peoples R China 2.Chinese Acad Sci, Wuhan Inst Phys & Math, Natl Ctr Magnet Resonance Wuhan, State Key Lab Magnet Resonance & Atom & Mol Phys, Wuhan 430071, Hubei, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Yao,Huang, Yongqi,Qin, Lingyun,et al. Effect of the Flexible Regions of the Oncoprotein Mouse Double Minute X on Inhibitor Binding Affinity[J]. BIOCHEMISTRY,2017,56(44):5943-5954. |
| APA | Chen, Yao.,Huang, Yongqi.,Qin, Lingyun.,Su, Zhengding.,Liu, Huili.,...&Zhou, Jingjing.(2017).Effect of the Flexible Regions of the Oncoprotein Mouse Double Minute X on Inhibitor Binding Affinity.BIOCHEMISTRY,56(44),5943-5954. |
| MLA | Chen, Yao,et al."Effect of the Flexible Regions of the Oncoprotein Mouse Double Minute X on Inhibitor Binding Affinity".BIOCHEMISTRY 56.44(2017):5943-5954. |
入库方式： OAI收割
来源：武汉物理与数学研究所
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