4yfk

Escherichia coli RNA polymerase in complex with squaramide compound 8.

spinqualitylabelsall models 4yfk, resolution 3.57Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4yfk is a 12 chain structure with sequence from Escherichia coli K-12 and Escherichia coli O139:H28 str. E24377A. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.571Å Ligands: 4C6, MG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RPOA_ECO24 DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. 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., <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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also RNA polymerase 3D structures Sigma factor 3D structures

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