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‘Conserved hypothetical’ proteins pose a challenge not just for functional genomics, but also to biology in general. As long as there
are hundreds of conserved proteins with unknown function in model organisms such as Escherichia coli, Bacillus subtilis or
Saccharomyces cerevisiae, any discussion towards a ‘complete’ understanding of these biological systems will remain a wishful
thinking. Insilico approaches exhibit great promise towards attempts that enable appreciating the plausible roles of these
hypothetical proteins. Among the majority of genomic proteins, two-thirds in unicellular organisms and more than 80% in
metazoa, are multi-domain proteins, created as a result of gene duplication events. Aromatic ring-hydroxylating dioxygenases, also
called Rieske dioxygenases (RDOs), are class of multi-domain proteins that catalyze the initial step in microbial aerobic
degradation of many aromatic compounds. Investigations here address the computational characterization of hypothetical proteins
containing Ferredoxin and Flavodoxin signatures. Consensus sequence of each class of oxidoreductase was obtained by a
phylogenetic analysis, involving clustering methods based on evolutionary relationship. A synthetic sequence was developed by
combining the consensus, which was used as the basis to search for their homologs via BLAST. The exercise yielded 129 multidomain
hypothetical proteins containing both 2Fe-2S (Ferredoxin) and FNR (Flavodoxin) domains. In the current study, 40 proteins
with N-terminus 2Fe-2S domain and C-terminus FNR domain are characterized, through homology modelling and docking
exercises which suggest dioxygenase activity indicating their plausible roles in degradation of aromatic moieties. 相似文献
2.
Lalitha Venkatramani Eric S Johnson Gundurao Kolavi Gillian M Air Wayne J Brouillette Blaine HM Mooers 《BMC structural biology》2012,12(1):1-11
Background
The quaternary structure of eukaryotic NADH:ubiquinone oxidoreductase (complex I), the largest complex of the oxidative phosphorylation, is still mostly unresolved. Furthermore, it is unknown where transiently bound assembly factors interact with complex I. We therefore asked whether the evolution of complex I contains information about its 3D topology and the binding positions of its assembly factors. We approached these questions by correlating the evolutionary rates of eukaryotic complex I subunits using the mirror-tree method and mapping the results into a 3D representation by multidimensional scaling.Results
More than 60% of the evolutionary correlation among the conserved seven subunits of the complex I matrix arm can be explained by the physical distance between the subunits. The three-dimensional evolutionary model of the eukaryotic conserved matrix arm has a striking similarity to the matrix arm quaternary structure in the bacterium Thermus thermophilus (rmsd=19 ?) and supports the previous finding that in eukaryotes the N-module is turned relative to the Q-module when compared to bacteria. By contrast, the evolutionary rates contained little information about the structure of the membrane arm. A large evolutionary model of 45 subunits and assembly factors allows to predict subunit positions and interactions (rmsd = 52.6 ?). The model supports an interaction of NDUFAF3, C8orf38 and C2orf56 during the assembly of the proximal matrix arm and the membrane arm. The model further suggests a tight relationship between the assembly factor NUBPL and NDUFA2, which both have been linked to iron-sulfur cluster assembly, as well as between NDUFA12 and its paralog, the assembly factor NDUFAF2.Conclusions
The physical distance between subunits of complex I is a major correlate of the rate of protein evolution in the complex I matrix arm and is sufficient to infer parts of the complex??s structure with high accuracy. The resulting evolutionary model predicts the positions of a number of subunits and assembly factors. 相似文献3.
‘Conserved hypothetical’ proteins pose a challenge not just for functional genomics, but also to biology in general. As long as there
are hundreds of conserved proteins with unknown function in model organisms such as Escherichia coli, Bacillus subtilis or
Saccharomyces cerevisiae, any discussion towards a ‘complete’ understanding of these biological systems will remain a wishful
thinking. Insilico approaches exhibit great promise towards attempts that enable appreciating the plausible roles of these
hypothetical proteins. Among the majority of genomic proteins, two-thirds in unicellular organisms and more than 80% in
metazoa, are multi-domain proteins, created as a result of gene duplication events. Aromatic ring-hydroxylating dioxygenases, also
called Rieske dioxygenases (RDOs), are class of multi-domain proteins that catalyze the initial step in microbial aerobic
degradation of many aromatic compounds. Investigations here address the computational characterization of hypothetical proteins
containing Ferredoxin and Flavodoxin signatures. Consensus sequence of each class of oxidoreductase was obtained by a
phylogenetic analysis, involving clustering methods based on evolutionary relationship. A synthetic sequence was developed by
combining the consensus, which was used as the basis to search for their homologs via BLAST. The exercise yielded 129 multidomain
hypothetical proteins containing both 2Fe-2S (Ferredoxin) and FNR (Flavodoxin) domains. In the current study, 17 proteins
with N-terminus FNR domain and C-terminus 2Fe-2S domain are characterized, through homology modelling and docking
exercises which suggest dioxygenase activity indicate their plausible roles in degradation of aromatic moieties. 相似文献
4.
A series of 2,6-disubstituted and 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles were synthesized, the structures of the compounds were elucidated and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system, antibacterial activity against Escherichia coli and Bacillus cirrhosis, and antifungal activity against Aspergillus niger and Penicillium wortmanni. Among the tested compounds 2-(2-furyl)-6-phenylimidazo[2,1-b][1,3,4] thiadiazole-5-carbaldehyde (6c) and (2-cyclohexyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methanol (7a) have shown the highest (100%) inhibitory activity. Compounds 6a, 6b, 7c, and 8a exhibited moderate antitubercular activity with percentage inhibition 36, 30, 15, and 20, respectively, at a MIC of >6.25 microg/ml. 相似文献
5.
Li Y Silamkoti A Kolavi G Mou L Gulati S Air GM Brouillette WJ 《Bioorganic & medicinal chemistry》2012,20(14):4582-4589
Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A series of influenza neuraminidase inhibitors with the pyrrolidinobenzoic acid scaffold containing lipophilic side chains at the C3 position have been synthesized and evaluated for influenza neuraminidase inhibitory activity. The size and geometry of the C3 side chains have been modified in order to investigate structure-activity relationships. The results indicated that size and geometry of the C3-side chain are important for selectivity of inhibition against N1 versus N2 NA, important type A influenza variants that infect man, including the highly lethal avian influenza. 相似文献
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