Structures and mechanism for the design of highly potent glucocorticoids
文献类型：期刊论文
| 作者 | He, Yuanzheng1; Yi, Wei2; Suino-Powell, Kelly1; Zhou, X. Edward1; Tolbert, W. David1; Tang, Xiaobo2; Yang, Jing3; Yang, Huaiyu3; Shi, Jingjing2 ; Hou, Li2
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| 刊名 | CELL RESEARCH
 |
| 出版日期 | 2014-06 |
| 卷号 | 24期号:6页码:713-726 |
| 关键词 | glucocorticoids glucocorticoid receptor potency cortisol mometasone furoate |
| ISSN号 | 1001-0602 |
| DOI | 10.1038/cr.2014.52 |
| 文献子类 | Article |
| 英文摘要 | The evolution of glucocorticoid drugs was driven by the demand of lowering the unwanted side effects, while keeping the beneficial anti-inflammatory effects. Potency is an important aspect of this evolution as many undesirable side effects are associated with use of high-dose glucocorticoids. The side effects can be minimized by highly potent glucocorticoids that achieve the same treatment effects at lower doses. This demand propelled the continuous development of synthetic glucocorticoids with increased potencies, but the structural basis of their potencies is poorly understood. To determine the mechanisms underlying potency, we solved the X-ray structures of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to its endogenous ligand, cortisol, which has relatively low potency, and a highly potent synthetic glucocorticoid, mometasone furoate (MF). The cortisol-bound GR LBD revealed that the flexibility of the C1-C2 single bond in the steroid A ring is primarily responsible for the low affinity of cortisol to GR. In contrast, we demonstrate that the very high potency of MF is achieved by its C-17 alpha furoate group completely filling the ligand-binding pocket, thus providing additional anchor contacts for high-affinity binding. A single amino acid in the ligand-binding pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol. Structure-based design led to synthesis of several novel glucocorticoids with much improved potency and efficacy. Together, these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing novel highly potent glucocorticoids. |
| WOS关键词 | LIGAND-BINDING DOMAIN ; TRANSCRIPTION FACTOR ; MOLECULAR-MECHANISMS ; FLUTICASONE FUROATE ; MOMETASONE FUROATE ; CHILDHOOD LEUKEMIA ; CRYSTAL-STRUCTURE ; KAPPA-B ; RECEPTOR ; MODULATION |
| 资助项目 | Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor[085P1000817] ; Office of Science of the US Department of Energy[DE-AC02-06CH11357] ; NIDDK/NIH fund[DK066202] ; NIDDK/NIH fund[DK071662] ; American Asthma Foundation fund, Amway (China),[00000000] ; National Natural Science Foundation of China[91217311] ; Chinese Postdoctoral Science Foundation[2012M511158] ; Chinese Postdoctoral Science Foundation[2013T60477] ; Jay and Betty Van Andel Foundation[00000000] |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5155289 |
| WOS记录号 | WOS:000337682900010 |
| 出版者 | INST BIOCHEMISTRY & CELL BIOLOGY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277045]  |
| 专题 | 药物靶标结构与功能中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Xu, H. Eric |
| 作者单位 | 1.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr, Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Discovery & Design, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | He, Yuanzheng,Yi, Wei,Suino-Powell, Kelly,et al. Structures and mechanism for the design of highly potent glucocorticoids[J]. CELL RESEARCH,2014,24(6):713-726. |
| APA | He, Yuanzheng.,Yi, Wei.,Suino-Powell, Kelly.,Zhou, X. Edward.,Tolbert, W. David.,...&Xu, H. Eric.(2014).Structures and mechanism for the design of highly potent glucocorticoids.CELL RESEARCH,24(6),713-726. |
| MLA | He, Yuanzheng,et al."Structures and mechanism for the design of highly potent glucocorticoids".CELL RESEARCH 24.6(2014):713-726. |
入库方式： OAI收割
来源：上海药物研究所
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