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Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (ROR gamma t) modulators: insights into different protein behaviors with "short" and "long" inverse agonists

文献类型：期刊论文

作者Yu, Ming-cheng6; Yang, Feng4,6; Ding, Xiao-yu4,5; Sun, Nan-nan3,6; Jiang, Zheng-yuan6; Huang, Ya-fei6; Yan, Yu-rong6; Zhu, Chen6; Xie, Qiong2,6; Chen, Zhi-feng4,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-11-25
页码11
ISSN号1671-4083
关键词RORγ t cocrystal structures MD simulation “ short” inverse agonists agonists “ long” inverse agonists
DOI10.1038/s41401-020-00552-w
通讯作者Luo, Xiao-min(xmluo@simm.ac.cn) ; Chen, Shi-jie(shijiechen@simm.ac.cn) ; Wang, Yong-hui(yonghuiwang@fudan.edu.cn)
英文摘要A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (ROR gamma t) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the "short" inverse agonist 6. With the increase in the size of the 6-position substituents, the "short" inverse agonist 6 first reversed its function to agonists and then to "long" inverse agonists. The cocrystal structures of ROR gamma t complexed with the representative "short" inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the "long" inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of "short" inverse agonist 6 and "long" inverse agonist 7h. To further reveal the molecular mechanisms of different ROR gamma t inverse agonists, we performed molecular dynamics simulations and found that "short" or "long" inverse agonists led to different behaviors of helixes H11, H11', and H12 of ROR gamma t. The "short" inverse agonist 6 destabilizes H11' and dislocates H12, while the "long" inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.
WOS关键词NUCLEAR RECEPTOR ; MECHANISM
资助项目National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[81573276] ; National Natural Science Foundation of China[81874287] ; National Natural Science Foundation of China[81973163] ; K. C. Wong Education ; Fudan-SIMM Joint Research Fund[FUSIMM20174007] ; CAS[XDA12020372] ; Shanghai Biopharmaceutical Science and Technology Supporting Plan[17431902100] ; Shanghai Biopharmaceutical Science and Technology Supporting Plan[19431900100] ; National Science and Technology Major Project[2018ZX09711002003-014] ; Natural Science Foundation of Shanghai[19ZR1436700] ; China Postdoctoral Science Foundation[2019M651383]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000592596500001
源URL[http://119.78.100.183/handle/2S10ELR8/292679]  
专题新药研究国家重点实验室
通讯作者Luo, Xiao-min; Chen, Shi-jie; Wang, Yong-hui
作者单位1.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Fudan Zhangjiang Inst, Shanghai 201203, Peoples R China
3.Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai 200032, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Ming-cheng,Yang, Feng,Ding, Xiao-yu,et al. Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (ROR gamma t) modulators: insights into different protein behaviors with "short" and "long" inverse agonists[J]. ACTA PHARMACOLOGICA SINICA,2020:11.
APA Yu, Ming-cheng.,Yang, Feng.,Ding, Xiao-yu.,Sun, Nan-nan.,Jiang, Zheng-yuan.,...&Wang, Yong-hui.(2020).Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (ROR gamma t) modulators: insights into different protein behaviors with "short" and "long" inverse agonists.ACTA PHARMACOLOGICA SINICA,11.
MLA Yu, Ming-cheng,et al."Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (ROR gamma t) modulators: insights into different protein behaviors with "short" and "long" inverse agonists".ACTA PHARMACOLOGICA SINICA (2020):11.

入库方式： OAI收割

来源：上海药物研究所

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