文献类型：期刊文献

英文题名：Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction

作者：Huang, Yunyuan[1];Xu, Yixiang[2];Song, Rongrong[1];Ni, Shuaishuai[3];Liu, Jiaqi[1];Xu, Yanhong[1];Ren, Yanliang[1];Rao, Li[1];Wang, Yingjie[4];Wei, Lin[1];Feng, Lingling[1];Su, Chen[5];Peng, Chao[5];Li, Jian[2];Wan, Jian[1]

机构：[1]Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol CCNU, Wuhan 430079, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Shanghai Univ Tradit Chinese Med, Canc Inst, Longhua Hosp, Shanghai 200237, Peoples R China;[4]Shenzhen Bay Lab, Shenzhen 518055, Guangdong, Peoples R China;[5]Natl Facil Prot Sci Shanghai, Zhangjiang Lab, Shanghai 201210, Peoples R China

年份：2020

卷号：63

期号：11

起止页码：6238

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000541741100032)】；

基金：This work was supported by the Natural Science Foundation of China (nos. 21877046, 21873035, 21572077, and 21472061), the Program for the PCSIRT (no. IRT0953), and the self-determined research funds of CCNU from the colleges' basic research and operation of MOE (nos. CCNU19TS011, CCNU18TS010, 2018YBZZ019, and CCNU16A02041). The support from the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) is also appreciated. We thank the staff of the BL19U1 beamline of the NCPSS at the Shanghai Synchrotron Radiation Facility for assistance during data collection.

语种：英文

摘要：Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of the allosteric inhibition mechanism reveals that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123-128), which in turn allows S123 to more easily form new hydrogen bonds with K71 and D74 in helix H3 (69-72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction.