Bioinformatyczna analiza struktury i oddziaływań z substratami metylotransferaz RNA odpowiedzialnych za oporność bakterii na antybiotyki
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2011-09-30T08:30:11Z
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Bioinformatics analysis of structure and interactions with substrates of RNA methyltransferases responsible for bacterial resistance to antbiotics
Abstract
Niniejsza praca doktorska dotyczyła badania interakcji metylotransferaz RNA z ich substratami i kofaktorami oraz projektowania inhibitorów ww. enzymów. W trakcie pracy badane były metylotransferazy Erm modyfikujące m6A2058 w 23S rRNA, odpowiedzialne za oporność bakterii na antybiotyki z grupy MLSB, metylotransferazy Rlm odpowiedzialne za oporność bakterii na tylozynę a modyfikujące m1G745 lub m1G748 w 23S rRNA i metylotransferazy Kam odpowiedzialne za oporność bakterii na aminoglikozydy a modyfikujące m1A1408 w 16S rRNA. W pracy zastosowano metody: symulacji dynamiki molekularnej, dokowania molekularnego, modelowania homologicznego i wirtualnych badań przesiewowych.W trakcie pracy przeanalizowano białko ErmC' i jego substrat RNA. Zbadano ruchy wewnątrzcząsteczkowe białka oraz zaproponowano model interakcji ErmC' z substratem i potencjalny inhibitor ww. enzymu. Zbadano oddziaływania białek Rlm z modyfikowaną przez nie helisą 35 w 23S rRNA. Zaproponowany został model interakcji ww. helisy z dimerem białka RlmA(I). Wymodelowana została struktura białka RlmA(II) oraz model oddziaływania tego enzymu z substratem RNA. Zaprojektowano także potencjalny inhibitor RlmA(II). Wykazano homologię enzymów Kam do metylotransferaz TrmB/Trm8 przeprowadzających metylację m7G. Stworzono model interakcji jednego z białek Kam – NpmA z rybosomem bakteryjnym i zaproponowano inhibitor NpmA.
This PhD thesis regarded investigation of interactions between RNA methyltransferases with their substrates and cofactors. It also concerned the designing of inhibitors of the enzymes mentioned above. Investigated methyltransferases included: Erm – modifying m6A2058 in 23S rRNA and responsible for bacterial resistance to MLSB antibiotics, Rlm – responsible for bacterial resistance to tylosin by modification of m1G745 or m1G748 in 23S rRNA and Kam – responsible for bacterial resistance to aminoglycosides by m1A1408 in 16S rRNA modification. Methods used: molecular dynamics, molecular docking, homology modelling and virtual ligand screening.ErmC' and its RNA substrate were investigated. Inner motions inside the protein were examined. A model of interactions between ErmC' and its RNA substrate was proposed. ErmC' inhibitor was designed. The interactions of Rlm proteins with 23S rRNA helix 35 were investigated. RlmA(II) structure was modelled. RNA substrate was docked to RlmA(II) model. A potential inhibitor of RlmA(II) was designed. The homology of Kam enzymes to TrmB/Trm8 methyltransferases methylating m7G was proved. A model of interaction NpmA (from Kam family) with a bacterial ribosome was suggested and NpmA inhibitor was designed.
This PhD thesis regarded investigation of interactions between RNA methyltransferases with their substrates and cofactors. It also concerned the designing of inhibitors of the enzymes mentioned above. Investigated methyltransferases included: Erm – modifying m6A2058 in 23S rRNA and responsible for bacterial resistance to MLSB antibiotics, Rlm – responsible for bacterial resistance to tylosin by modification of m1G745 or m1G748 in 23S rRNA and Kam – responsible for bacterial resistance to aminoglycosides by m1A1408 in 16S rRNA modification. Methods used: molecular dynamics, molecular docking, homology modelling and virtual ligand screening.ErmC' and its RNA substrate were investigated. Inner motions inside the protein were examined. A model of interactions between ErmC' and its RNA substrate was proposed. ErmC' inhibitor was designed. The interactions of Rlm proteins with 23S rRNA helix 35 were investigated. RlmA(II) structure was modelled. RNA substrate was docked to RlmA(II) model. A potential inhibitor of RlmA(II) was designed. The homology of Kam enzymes to TrmB/Trm8 methyltransferases methylating m7G was proved. A model of interaction NpmA (from Kam family) with a bacterial ribosome was suggested and NpmA inhibitor was designed.
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Wydział Biologii: Instytut Biologii Molekularnej i Biotechnologii
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metylotransferazy, methyltransferases, metylacja, methylation, oporność, resistance, antybiotyki, antibiotics