文献类型：期刊文献

英文题名：Computational prediction and validation of specific EmbR binding site on PknH

作者：Na, Insung[1,9];Dai, Huanqin[1,3];Li, Hantian[3,7];Gupta, Anvita[4];Kreda, David[5];Zhang, Powell[8];Chen, Xiangyin[6];Zhang, Lixin[6];Alterovitz, Gil[2]

机构：[1]Harvard Med Sch, Computat Hlth Informat Program, Boston Childrens Hosp, Boston, MA 02115 USA;[2]Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA;[3]Inst Microbiol, State Key Lab Mycol, Beijing 100101, Peoples R China;[4]Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA;[5]Harvard Med Sch, Ctr Biomed Informat, Boston, MA 02115 USA;[6]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[7]Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA;[8]Lexington High Sch, Boston, MA 02115 USA;[9]HITS Inc, 124 Teheran Ro, Seoul 06234, South Korea

年份：2021

卷号：6

期号：4

起止页码：429

外文期刊名：SYNTHETIC AND SYSTEMS BIOTECHNOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000751765600002)】；

基金：This work was supported by the National Institutes of Health Grant No. 7R01GM118467-05 and the National Natural Science Foundation of China (31720103901). We would like to thank Mr. J ames Jones in Boston Children's Hospital and Ms. Ning Xie in Brigham and Women's Hospital for critical reading and helpful discussions.

语种：英文

外文关键词：Disorder-to-order transition; Protein intrinsic disorder; Binding site prediction; Drug resistance; Molecular simulation

摘要：Tuberculosis drug resistance continues to threaten global health but the underline molecular mechanisms are not clear. Ethambutol (EMB), one of the well-known first - line drugs in tuberculosis treatment is, unfortunately, not free from drug resistance problems. Genomic studies have shown that some genetic mutations in Mycobacterium tuberculosis (Mtb) EmbR, and EmbC/A/B genes cause EMB resistance. EmbR-PknH pair controls embC/A/B operon, which encodes EmbC/A/B genes, and EMB interacts with EmbA/B proteins. However, the EmbR binding site on PknH was unknown. We conducted molecular simulation on the EmbR- peptides binding structures and discovered phosphorylated PknH 273-280 (N '-HEALSPDPD-C ') makes beta strand with the EmbR FHA domain, as beta-MoRF (MoRF; molecular recognition feature) does at its binding site. Hydrogen bond number analysis also supported the peptides' beta-MoRF forming activity at the EmbR FHA domain. Also, we discovered that previously known phosphorylation residues might have their chronological order according to the phosphorylation status. The discovery validated that Mtb PknH 273-280 (N '-HEALSDPD-C ') has reliable EmbR binding affinity. This approach is revolutionary in the computer-aided drug discovery field, because it is the first trial to discover the protein-protein interaction site, and find binding partner in nature from this site.