Computational prediction and validation of specific EmbR binding site on PknH

查看全文 作　　者：Insung [1]Na;Huanqin [1,3]Dai;Hantian [3,7]Li;Anvita [4]Gupta;David [5]Kreda;Powell [8]Zhang;Xiangyin [6]Chen;Lixin [6]Zhang;Gil [2]Alterovitz 机构地区：[1]Computational Health Informatics Program,Boston Children’s Hospital/Harvard Medical School,Boston,MA 02115,USA;[2]Department of Medicine,Brigham and Women’s Hospital/Harvard Medical School,Boston,MA 02115,USA;[3]State Key Laboratory of Mycology,Institute of Microbiology,Beijing,100101 China;[4]Department of Computer Sciences,Stanford University,Stanford CA 94305,USA;[5]Center for Biomedical Informatics,Harvard Medical School,Boston,MA 02115,USA;[6]State Key Laboratory of Bioreactor Engineering,East China University of Science and Technology,Shanghai,China;[7]Department of Biology,The Johns Hopkins University,Baltimore,MD 21218,USA;[8]Lexington High School,Boston,MA 02115,USA 出　　处：《Synthetic and Systems Biotechnology》索引2021年第6卷第4期,共8页 基　　金：This work was supported by the National Institutes of Health Grant No.7R01GM118467-05;the National Natural Science Foundation of China(31720103901). 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′-HEALS^(P)DPD-C′)makesβstrand with the EmbR FHA domain,asβ-MoRF(MoRF;molecular recognition feature)does at its binding site.Hydrogen bond number analysis also supported the peptides’β-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. 关 键 词：Disorder-to-order transition Protein intrinsic disorder Binding site prediction Drug resistance Molecular simulation