7szk

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Cryo-EM structure of 27a bound to E. coli RNAP and rrnBP1 promoter complex

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Categories: Escherichia coli K-12 | Large Structures | Murakami KS | Shin Y

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 == Structural highlights ==
 <table><tr><td colspan='2'>[[7szk]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SZK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SZK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D9X:(2S,7R,7aR,13aP,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-5,21,23-trihydroxy-27-methoxy-2,4,16,20,22,24,26-heptamethyl-10-[4-(2-methylpropyl)piperazin-1-yl]-12-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1,6,15-trioxo-1,2,7,7a-tetrahydro-6H-2,7-(epoxypentadeca[1,11,13]trienoimino)[1]benzofuro[4,5-a]phenoxazin-25-yl+acetate'>D9X</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.94&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D9X:(2S,7R,7aR,13aP,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-5,21,23-trihydroxy-27-methoxy-2,4,16,20,22,24,26-heptamethyl-10-[4-(2-methylpropyl)piperazin-1-yl]-12-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1,6,15-trioxo-1,2,7,7a-tetrahydro-6H-2,7-(epoxypentadeca[1,11,13]trienoimino)[1]benzofuro[4,5-a]phenoxazin-25-yl+acetate'>D9X</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7szk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7szk OCA], [https://pdbe.org/7szk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7szk RCSB], [https://www.ebi.ac.uk/pdbsum/7szk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7szk ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/RPOA_ECOLI RPOA_ECOLI]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit plays an important role in subunit assembly since its dimerization is the first step in the sequential assembly of subunits to form the holoenzyme.[HAMAP-Rule:MF_00059]
+[https://www.uniprot.org/uniprot/RPOA_ECOLI RPOA_ECOLI] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. This subunit plays an important role in subunit assembly since its dimerization is the first step in the sequential assembly of subunits to form the holoenzyme.[HAMAP-Rule:MF_00059]
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Rifampin (RMP), a very potent inhibitor of the Mycobacterium tuberculosis (MTB) RNA polymerase (RNAP), remains a keystone in the treatment of tuberculosis since its introduction in 1965. However, rifamycins suffer from serious drawbacks, including 3- to 9-month treatment times, Cyp450 induction (particularly problematic for HIV-MTB coinfection), and resistant mutations within RNAP that yield RIF-resistant (RIF(R)) MTB strains. There is a clear and pressing need for improved TB therapies. We have utilized a structure-based drug design approach to synthesize and test novel benzoxazinorifamycins (bxRIF), congeners of the clinical candidate rifalazil. Our goal is to gain binding interactions that will compensate for the loss of RIF-binding affinity to the (RIF(R)) MTB RNAP and couple those with substitutions that we have previously found that essentially eliminate Cyp450 induction. Herein, we report a systematic exploration of 42 substituted bxRIFs that have yielded an analogue (27a) that has an excellent in vitro activity (MTB RNAP inhibition, MIC, MBC), enhanced ( approximately 30-fold &gt; RMP) activity against RIF(R) MTB RNAP, negligible hPXR activation, good mouse pharmacokinetics, and excellent activity with no observable adverse effects in an acute mouse TB model. In a time-kill study, 27a has a 7 day MBC that is approximately 10-fold more potent than RMP. These results suggest that 27a may exhibit a faster kill rate than RMP, which could possibly reduce the clinical treatment time. Our synthetic protocol enabled the synthesis of approximately 2 g of 27a at &gt;95% purity in 3 months, demonstrating the feasibility of scale-up synthesis of bxRIFs for preclinical and clinical studies.
-Optimization of Benzoxazinorifamycins to Improve Mycobacterium tuberculosis RNA Polymerase Inhibition and Treatment of Tuberculosis.,Rajeswaran W, Ashkar SR, Lee PH, Yeomans L, Shin Y, Franzblau SG, Murakami KS, Showalter HD, Garcia GA ACS Infect Dis. 2022 Aug 12;8(8):1422-1438. doi: 10.1021/acsinfecdis.1c00636., Epub 2022 Jun 30. PMID:35772744<ref>PMID:35772744</ref>
+==See Also==
+*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+*[[Sigma factor 3D structures|Sigma factor 3D structures]]
-</div>
-<div class="pdbe-citations 7szk" style="background-color:#fffaf0;"></div>
-== References ==
-<references/>
 __TOC__
 </StructureSection>

7szk

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Cryo-EM structure of 27a bound to E. coli RNAP and rrnBP1 promoter complex

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Function

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