Sandbox Reserved 1051: Difference between revisions

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[[Image:ebselen pic.jpg |100 xp|left|thumb|'''Figure 4.''']]

<scene name='69/694218/~~Ag85c-ebselen~~/1'>Ag85C-~~ebselen~~</scene> (Figure 3) is characterized by a covalent bond between [http://en.wikipedia.org/wiki/Ebselen ebselen] and Cys209, thus forcing the otherwise kinked helix α-9 to take on a relaxed conformation (Figure 3). This allows movement of the helix and causes disruption of the hydrogen bonds within the catalytic triad, ultimately inactivating Ag85C.<ref name="Favrot"/>

<scene name='69/694218/Ebselen/1'>Ag85C-Ebselen</scene> (Figure 3) is characterized by a covalent bond between [http://en.wikipedia.org/wiki/Ebselen ebselen] and Cys209, thus forcing the otherwise kinked helix α-9 to take on a relaxed conformation (Figure 3). This allows movement of the helix and causes disruption of the hydrogen bonds within the catalytic triad, ultimately inactivating Ag85C.<ref name="Favrot"/>

These initial findings suggest that ebselen-like mutants characterized by alterations in Cys209 may serve as potential drug targets for ''M. tuberculosis''. Because any modification or mutation of Cys209 in Ag85C leads to either a dramatic decrease or complete loss of enzymatic activity, research suggests there is a low probability of ''M. tuberculosis'' developing resistance to a drug modifying the Cys209. The structures and results of the following mutations and modifications support a strategy for inhibiting the Ag85 complex as a whole with mechanism-based inhibitors that first react with Ser124 to promote the relaxation of helix α-9 and expose Cys209 and then react with Cys209 side chain thiol to covalently modify this conserved residue. Such a bifunctional inhibitor would offer specificity while minimizing the probability of selecting for drug resistant mutants.<ref name="Favrot"/>

Sandbox Reserved 1051: Difference between revisions

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@@ Line 34: / Line 34: @@
 [[Image:ebselen pic.jpg |100 xp|left|thumb|'''Figure 4.''']]
-<scene name='69/694218/Ag85c-ebselen/1'>Ag85C-ebselen</scene> (Figure 3) is characterized by a covalent bond between [http://en.wikipedia.org/wiki/Ebselen ebselen] and Cys209, thus forcing the otherwise kinked helix α-9 to take on a relaxed conformation (Figure 3). This allows movement of the helix and causes disruption of the hydrogen bonds within the catalytic triad, ultimately inactivating Ag85C.<ref name="Favrot"/>
+<scene name='69/694218/Ebselen/1'>Ag85C-Ebselen</scene> (Figure 3) is characterized by a covalent bond between [http://en.wikipedia.org/wiki/Ebselen ebselen] and Cys209, thus forcing the otherwise kinked helix α-9 to take on a relaxed conformation (Figure 3). This allows movement of the helix and causes disruption of the hydrogen bonds within the catalytic triad, ultimately inactivating Ag85C.<ref name="Favrot"/>
 These initial findings suggest that ebselen-like mutants characterized by alterations in Cys209 may serve as potential drug targets for ''M. tuberculosis''.  Because any modification or mutation of Cys209 in Ag85C leads to either a dramatic decrease or complete loss of enzymatic activity, research suggests there is a low probability of ''M. tuberculosis'' developing resistance to a drug modifying the Cys209.  The structures and results of the following mutations and modifications support a strategy for inhibiting the Ag85 complex as a whole with mechanism-based inhibitors that first react with Ser124 to promote the relaxation of helix α-9 and expose Cys209 and then react with Cys209 side chain thiol to covalently modify this conserved residue.  Such a bifunctional inhibitor would offer specificity while minimizing the probability of selecting for drug resistant mutants.<ref name="Favrot"/>