Sandbox Reserved 1053: Difference between revisions

Due to the importance of Ag85C enzymatic activity in maintaining the integrity of the ''Mycobacteria tuberculosis'' cell wall though mycolic acid modifications, the Ag85C enzyme represents a potentially effective avenue for inhibiting cell growth. The conformational sensitivity of the active site residues, H260, E228, and S124, relies entirely upon Van der Waals interaction between C209 and L232-T 231 (Figure #). The C209 facilitated interaction causes the <scene name='69/694220/Alpha_9_helix/2'>α9 helix</scene> to acquire a kinked conformation that promotes optimal interaction distances between catalytic residues. As a result, C209 has been a specific target residue for Ag85C inhibition.

Ag85C can be inhibited by [http://en.wikipedia.org/wiki/Ebselen ebselen] covalently bound to the sulfur of C209. Ebselen is a thiol-modifying agent that serves as an electrophile for the C209 that results in a sulfur-selenium bond. 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-T31, which effectively disrupts the interaction that holds the α9 helix in the active conformation. Furthermore, the bulk of ebselen creates steric hindrance with the α9 helix residues (Figure #). Relaxation of the α9 helix removes E228 and H260, which now interacts with S148, from the active site. The absence of these residues decreases the nucleophilicity of the S124 alcohol which decreases serine hydrolytic activity.