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

doi:10.1038/s41401-020-00552-w

	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
	Yu, Ming-cheng 5; Yang, Feng 1,5; Ding, Xiao-yu 1,6; Sun, Nan-nan 3,5; Jiang, Zheng-yuan 5; Huang, Ya-fei 5; Yan, Yu-rong 5; Zhu, Chen 5; Xie, Qiong 2,5; Chen, Zhi-feng 1,6
刊名	ACTA PHARMACOLOGICA SINICA
	2020-11-25
页码	11
关键词	RORγ t cocrystal structures MD simulation “ short” inverse agonists agonists “ long” inverse agonists
ISSN号	1671-4083
DOI	10.1038/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.
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关键词	NUCLEAR RECEPTOR ; MECHANISM
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000592596500001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292679]
专题	中国科学院上海药物研究所
通讯作者	Luo, Xiao-min; Chen, Shi-jie; Wang, Yong-hui
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, 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.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China 6.Univ Chinese Acad Sci, Beijing 100049, 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.