Sandbox Reserved 1053: Difference between revisions

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OCA, Ben Zercher, Geoffrey C. Hoops, Katelyn Baumer, Mary Liggett, Jakob Jozwiakowski

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-Ag85C can be inhibited by [http://en.wikipedia.org/wiki/Ebselen ebselen], which covalently bounds to the sulfur in C209. Ebselen is a thiol-modifying agent that serves as an electrophile for a C209 nucleophilic attack that results in sulfur-selenium bond formation. Co-crystallization of ebselen with Ag85C provides an explanation for the mechanism of ebselen-based inhibition. The addition of ebselen increases the distance between C209 and L232-T231, which effectively disrupts the interaction that holds the α9 helix in the active conformation. The disruption of this interaction causes the α9 helix to <scene name='69/694220/Inhibited_relaxed_helix/1'>relaxe</scene>. Furthermore, the bulk of ebselen creates steric hindrance with the α9 helix residues, which can be seen in the figure to the right. The pink helix represents the native enzyme, and the tan helix represents Ag85C complexed with ebselen, which is shown in green. Relaxation of the α9 helix due to ebselen removes E228 and H260, which now interacts with S148, from the active site. The absence of these residues destroys the charge relay mechanism, and as a result, the nucleophilicity of the S124 alcohol is not longer strengthened, which decreases serine hydrolytic activity.
+Ag85C can be inhibited by [http://en.wikipedia.org/wiki/Ebselen ebselen], which covalently bounds to the sulfur in C209. Ebselen is a thiol-modifying agent that serves as an electrophile for a C209 nucleophilic attack that results in sulfur-selenium bond formation. Co-crystallization of ebselen with Ag85C provides an explanation for the mechanism of ebselen-based inhibition. The addition of ebselen increases the distance between C209 and L232-T231, which effectively disrupts the interaction that holds the α9 helix in the active conformation. The disruption of this interaction causes the α9 helix to <scene name='69/694220/Inhibited_relaxed_helix/1'>relax</scene>. Furthermore, the bulk of ebselen creates steric hindrance with the α9 helix residues, which can be seen in the figure to the right. The pink helix represents the native enzyme, and the tan helix represents Ag85C complexed with ebselen, which is shown in green. Relaxation of the α9 helix due to ebselen removes E228 and H260, which now interacts with S148, from the active site. The absence of these residues destroys the charge relay mechanism, and as a result, the nucleophilicity of the S124 alcohol is not longer strengthened, which decreases serine hydrolytic activity.
-Relaxed alpha helix scene <scene name='69/694220/Inhibited_relaxed_helix/1'>relaxed</scene>
 ===Inhibitors===