PhoP-PhoQ: Difference between revisions
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In this structure, <scene name='Sandbox_Reserved_344/P-analog/1'>Beryllofluoride</scene> (BeF<sub>3</sub><sup>-</sup>) is used as a phosphoryl analog to induce the active state conformation. There are numerous bonds that form as a result of BeF<sub>3</sub><sup>-</sup> coordination. F<sub>1</sub> of BeF<sub>3</sub><sup>-</sup> helps satisfy the octahedral coordination of a present active site <scene name='PhoP-PhoQ/Mg-f1/4'>Mg</scene><sup>2+</sup>. The conserved active site lysine, <scene name='PhoP-PhoQ/Lys101-f3/2'>Lys101</scene>, forms important intramolecular and intermolecular salt bridges, one of which is with F<sub>3</sub> of BeF<sub>3</sub><sup>-</sup>. A conserved "switch residue" <scene name='PhoP-PhoQ/Thr79-f2/2'>Thr79</scene>, involved in the activation of all response regulators, forms a H-bond with F<sub>2</sub> of BeF<sub>3</sub><sup>-</sup>. F<sub>2</sub> of BeF<sub>3</sub><sup>-</sup> also forms a H-bond with the backbone nitrogen atom of <scene name='PhoP-PhoQ/Gly53-f2/3'>Gly53</scene>.<ref name=Bachhawat>PMID:17545283</ref> | In this structure, <scene name='Sandbox_Reserved_344/P-analog/1'>Beryllofluoride</scene> (BeF<sub>3</sub><sup>-</sup>) is used as a phosphoryl analog to induce the active state conformation. There are numerous bonds that form as a result of BeF<sub>3</sub><sup>-</sup> coordination. F<sub>1</sub> of BeF<sub>3</sub><sup>-</sup> helps satisfy the octahedral coordination of a present active site <scene name='PhoP-PhoQ/Mg-f1/4'>Mg</scene><sup>2+</sup>. The conserved active site lysine, <scene name='PhoP-PhoQ/Lys101-f3/2'>Lys101</scene>, forms important intramolecular and intermolecular salt bridges, one of which is with F<sub>3</sub> of BeF<sub>3</sub><sup>-</sup>. A conserved "switch residue" <scene name='PhoP-PhoQ/Thr79-f2/2'>Thr79</scene>, involved in the activation of all response regulators, forms a H-bond with F<sub>2</sub> of BeF<sub>3</sub><sup>-</sup>. F<sub>2</sub> of BeF<sub>3</sub><sup>-</sup> also forms a H-bond with the backbone nitrogen atom of <scene name='PhoP-PhoQ/Gly53-f2/3'>Gly53</scene>.<ref name=Bachhawat>PMID:17545283</ref> | ||
===Spontaneous Dimerization=== | |||
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Spontaneous dimerization of the unactivated phoP regulatory domain can be observed in vitro, but is likely due to high concentration of the protein and may not occur in vivo. Although the dimerization of the unactivated phoP regulatory domain results in a homodimer similar to the activated homodimer, it is significantly less stable. Activation by the phosphoryl group helps to stabilize the α-4 helix, β-5 sheet and α-5 helix dimerization interphase. Without the phosphoryl group, the two monomers dimerize in an asymmetric fashion that lends to molecular instability. | |||
</StructureSection> | </StructureSection> | ||
===PhoP-PhoQ and Virulence=== | ===PhoP-PhoQ and Virulence=== | ||
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Pathogenic bacteria seldom express virulence genes constitutively, they instead need to be able to express the correct virulence genes in the correct environment. Not all virulence factors confer a selective advantage to the microbe at the same stage of infection. Thus, it is the job of the phoP-phoQ system to modulate virulence gene expression according to the cellular micro-environment.<ref name=Hoch>PMID:10745001</ref> | Pathogenic bacteria seldom express virulence genes constitutively, they instead need to be able to express the correct virulence genes in the correct environment. Not all virulence factors confer a selective advantage to the microbe at the same stage of infection. Thus, it is the job of the phoP-phoQ system to modulate virulence gene expression according to the cellular micro-environment.<ref name=Hoch>PMID:10745001</ref> | ||
A particular and well studied environmental factor relative to the phoP-phoQ system is [Mg<sup>2+</sup>]. In response to low [Mg<sup>2+</sup>], such as would be found inside a macrophage phagosome, phoQ autophosphorylates and transphorphorylates phoP. PhoP then binds to the bacterial DNA and simultaneously activates the expression of pags (phoP activated genes) and represses the expression of prgs (phoP repressed genes). Among the gene products of pags are proteins necessary to survive inside the macrophage, a critical stage of ''Salmonella Typhirium'' virulence. Among the gene products of prgs are proteins necessary for invasion and infection of the host, which are less important once in a host macrophage's phagosome. | A particular and well studied environmental factor relative to the phoP-phoQ system is [Mg<sup>2+</sup>]. In response to low [Mg<sup>2+</sup>], such as would be found inside a macrophage phagosome, phoQ autophosphorylates and transphorphorylates phoP. PhoP then binds to the bacterial DNA and simultaneously activates the expression of pags (phoP activated genes) and represses the expression of prgs (phoP repressed genes). Among the gene products of pags are proteins necessary to survive inside the macrophage, a critical stage of ''Salmonella Typhirium'' virulence. Among the gene products of prgs are proteins necessary for invasion and infection of the host, which are less important once in a host macrophage's phagosome. | ||
Two component regulatory systems such as phoP-phoQ are obviously an attractive target for future antimicrobial drugs. If the phoP-phoQ can be altered to a dysfunctional state, the relevant bacteria would have decreased pathogenicity and increased suceptibility to nonspecific immune defense. | |||
== 3D Structures of PhoP-PhoQ== | == 3D Structures of PhoP-PhoQ== | ||