Sixteen pairs of two-component regulatory systems are identified in the genome of Staphylococcus epidermidis ATCC12228 strain, which is newly sequenced by our laboratory for Medical Molecular Virology and Chinese Nati...Sixteen pairs of two-component regulatory systems are identified in the genome of Staphylococcus epidermidis ATCC12228 strain, which is newly sequenced by our laboratory for Medical Molecular Virology and Chinese National Human Genome Center at Shanghai, by using bio- informatics analysis. Comparative analysis of the two- component regulatory systems in S. epidermidis and that of S. aureus and Bacillus subtilis shows that these systems may regulate some important biological functions, e.g. growth, biofilm formation, and expression of virulence factors in S. epidermidis. Two conserved domains, i.e. HATPase_c and REC domains, are found in all 16 pairs of two-component proteins. Homologous modelling analysis indicates that there are 4 similar HATPase_c domain structures of histidine kinases and 13 similar REC domain structures of response regulators, and there is one AMP-PNP binding pocket in the HATPase_c domain and three active aspartate residues in the REC domain. Preliminary experiment reveals that the bioinfor- matics analysis of the conserved domain structures in the two-component regulatory systems in S. epidermidis may provide useful information for discovery of potential drug target.展开更多
Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be ...Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.展开更多
Prediction of protein functions from known genomic sequences is an important mission of bioinformatics. One approach is to classify proteins into functional catego- ries. We have therefore developed a method based on ...Prediction of protein functions from known genomic sequences is an important mission of bioinformatics. One approach is to classify proteins into functional catego- ries. We have therefore developed a method based on protein domain composition and the maximum likelihood estimation (MLE) algorithm to classify proteins according to functions. Using the Saccharomyces cerevisiae genome, we compared the effectiveness of the MLE approach with that of an intui- tive and simple method. The MLE method outperformed the simple method, achieving an estimated specificity of 75.45% and an estimated sensitivity of 40.26%. These results indicate that domain is an important feature of proteins and is closely related to protein function.展开更多
文摘Sixteen pairs of two-component regulatory systems are identified in the genome of Staphylococcus epidermidis ATCC12228 strain, which is newly sequenced by our laboratory for Medical Molecular Virology and Chinese National Human Genome Center at Shanghai, by using bio- informatics analysis. Comparative analysis of the two- component regulatory systems in S. epidermidis and that of S. aureus and Bacillus subtilis shows that these systems may regulate some important biological functions, e.g. growth, biofilm formation, and expression of virulence factors in S. epidermidis. Two conserved domains, i.e. HATPase_c and REC domains, are found in all 16 pairs of two-component proteins. Homologous modelling analysis indicates that there are 4 similar HATPase_c domain structures of histidine kinases and 13 similar REC domain structures of response regulators, and there is one AMP-PNP binding pocket in the HATPase_c domain and three active aspartate residues in the REC domain. Preliminary experiment reveals that the bioinfor- matics analysis of the conserved domain structures in the two-component regulatory systems in S. epidermidis may provide useful information for discovery of potential drug target.
基金supported by the National Key R&D Program of China(grant no.2022YFF1203005)the National Natural Science Foundation of China(22237005,81903458,82273425)+1 种基金Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20212700,China)China Postdoctoral Science Foundation(2019M660090)。
文摘Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.
文摘Prediction of protein functions from known genomic sequences is an important mission of bioinformatics. One approach is to classify proteins into functional catego- ries. We have therefore developed a method based on protein domain composition and the maximum likelihood estimation (MLE) algorithm to classify proteins according to functions. Using the Saccharomyces cerevisiae genome, we compared the effectiveness of the MLE approach with that of an intui- tive and simple method. The MLE method outperformed the simple method, achieving an estimated specificity of 75.45% and an estimated sensitivity of 40.26%. These results indicate that domain is an important feature of proteins and is closely related to protein function.
