View source for 4yfn


==Escherichia coli RNA polymerase in complex with squaramide compound 14 (N-[3,4-dioxo-2-(4-{[4-(trifluoromethyl)benzyl]amino}piperidin-1-yl)cyclobut-1-en-1-yl]-3,5-dimethyl-1,2-oxazole-4-sulfonamide)==
<StructureSection load='4yfn' size='340' side='right'caption='[[4yfn]], [[Resolution|resolution]] 3.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4yfn]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12] and [https://en.wikipedia.org/wiki/Escherichia_coli_O139:H28_str._E24377A Escherichia coli O139:H28 str. E24377A]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YFN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.817&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4C2:N-[3,4-DIOXO-2-(4-{[4-(TRIFLUOROMETHYL)BENZYL]AMINO}PIPERIDIN-1-YL)CYCLOBUT-1-EN-1-YL]-3,5-DIMETHYL-1,2-OXAZOLE-4-SULFONAMIDE'>4C2</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=4yfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yfn OCA], [https://pdbe.org/4yfn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yfn RCSB], [https://www.ebi.ac.uk/pdbsum/4yfn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yfn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RPOD_ECOLI RPOD_ECOLI] Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This is the primary sigma factor of this bacterium.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human plasma protein from below minimum detection levels, i.e., &lt;1% to 4-6%, while retaining biochemical potency. Since in vitro antimicrobial activity against an efflux-negative strain of Haemophilus influenzae was 4- to 8-fold higher, the combined improvement was at least 20- to 60-fold. Cocrystal structures of Escherichia coli RNA polymerase with two key squaramides showed displacement of the switch 2, predicted to interfere with the conformational change of the clamp domain and/or with binding of template DNA, a mechanism akin to that of natural product myxopyronin. Furthermore, the structures confirmed the chemical features required for biochemical potency. The terminal isoxazole and benzyl rings bind into distinct relatively narrow, hydrophobic pockets, and both are required for biochemical potency. In contrast, the linker composed of squarate and piperidine accesses different conformations in their respective cocrystal structures with RNA polymerase, reflecting its main role of proper orientation of the aforementioned terminal rings. These observations further explain the tolerance of hydrophilic substitutions in the linker region that was exploited to improve the fraction unbound to human plasma protein while retaining biochemical potency.

X-ray Crystal Structures of Escherichia coli RNA Polymerase with Switch Region Binding Inhibitors Enable Rational Design of Squaramides with an Improved Fraction Unbound to Human Plasma Protein.,Molodtsov V, Fleming PR, Eyermann CJ, Ferguson AD, Foulk MA, McKinney DC, Masse CE, Buurman ET, Murakami KS J Med Chem. 2015 Mar 23. PMID:25798859<ref>PMID:25798859</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4yfn" style="background-color:#fffaf0;"></div>

==See Also==
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
*[[Sigma factor 3D structures|Sigma factor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli K-12]]
[[Category: Escherichia coli O139:H28 str. E24377A]]
[[Category: Large Structures]]
[[Category: Buurman ET]]
[[Category: Eyermann CJ]]
[[Category: Ferguson AD]]
[[Category: Fleming PR]]
[[Category: Foulk MA]]
[[Category: Masse CE]]
[[Category: McKinney DC]]
[[Category: Molodtsov V]]
[[Category: Murakami KS]]