Computational prediction and validation of specific EmbR binding site on PknH
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...
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KeAi Communications Co., Ltd.
2021
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oai:doaj.org-article:29352371b14e43a29dac924421ad89212021-11-28T04:34:44ZComputational prediction and validation of specific EmbR binding site on PknH2405-805X10.1016/j.synbio.2021.11.006https://doaj.org/article/29352371b14e43a29dac924421ad89212021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2405805X21000740https://doaj.org/toc/2405-805XTuberculosis 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 β strand with the EmbR FHA domain, as β-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.Insung NaHuanqin DaiHantian LiAnvita GuptaDavid KredaPowell ZhangXiangyin ChenLixin ZhangGil AlterovitzKeAi Communications Co., Ltd.articleDisorder-to-order transitionProtein intrinsic disorderBinding site predictionDrug resistanceMolecular simulationBiotechnologyTP248.13-248.65Biology (General)QH301-705.5ENSynthetic and Systems Biotechnology, Vol 6, Iss 4, Pp 429-436 (2021) |
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EN |
| topic |
Disorder-to-order transition Protein intrinsic disorder Binding site prediction Drug resistance Molecular simulation Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 |
| spellingShingle |
Disorder-to-order transition Protein intrinsic disorder Binding site prediction Drug resistance Molecular simulation Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Insung Na Huanqin Dai Hantian Li Anvita Gupta David Kreda Powell Zhang Xiangyin Chen Lixin Zhang Gil Alterovitz Computational prediction and validation of specific EmbR binding site on PknH |
| description |
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 β strand with the EmbR FHA domain, as β-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. |
| format |
article |
| author |
Insung Na Huanqin Dai Hantian Li Anvita Gupta David Kreda Powell Zhang Xiangyin Chen Lixin Zhang Gil Alterovitz |
| author_facet |
Insung Na Huanqin Dai Hantian Li Anvita Gupta David Kreda Powell Zhang Xiangyin Chen Lixin Zhang Gil Alterovitz |
| author_sort |
Insung Na |
| title |
Computational prediction and validation of specific EmbR binding site on PknH |
| title_short |
Computational prediction and validation of specific EmbR binding site on PknH |
| title_full |
Computational prediction and validation of specific EmbR binding site on PknH |
| title_fullStr |
Computational prediction and validation of specific EmbR binding site on PknH |
| title_full_unstemmed |
Computational prediction and validation of specific EmbR binding site on PknH |
| title_sort |
computational prediction and validation of specific embr binding site on pknh |
| publisher |
KeAi Communications Co., Ltd. |
| publishDate |
2021 |
| url |
https://doaj.org/article/29352371b14e43a29dac924421ad8921 |
| work_keys_str_mv |
AT insungna computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT huanqindai computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT hantianli computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT anvitagupta computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT davidkreda computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT powellzhang computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT xiangyinchen computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT lixinzhang computationalpredictionandvalidationofspecificembrbindingsiteonpknh AT gilalterovitz computationalpredictionandvalidationofspecificembrbindingsiteonpknh |
| _version_ |
1718408306920259584 |