alpha- AMANITIN
The most potent and specific known inhibitor of the enzyme RNA polymerase is a-amanitin. The ‘‘death cap’’ Amanita phalloides mushroom yeilds a-amanitin, which blocks both transcription initiation and elongation. The structure of the cocrystal (Model 1) of poison/polymerase suggests that a–amanitin interferes with a protein conformational change underlying the transcription mechanism. Pope Clement VII died in 1534 from eating this deadly toxin C39H54N10O14S (Formula for a–amanitin)
What could this harmless looking mushroom possibly posses that could kill within ten days of consumption a human being?
As we’ve seen in the detailed description of transcription the bridge helix that forms between the Rpb1 and 2 domains of RNAP is essential for positioning and moving the RNA DNA hybrid in the enzyme. a–amanitin happens to bind right to that bridge directly and indirectly inhibiting the ever so important conformational changes associated with the protein. Hydroxyproline 2 of a–amanitin binds directly to Glu822 of the helix. 4,5 dihydroxyisoleucine 3 of a–amanitin hydrogen bonds to Gln768, which is hydrogen bonded to His816 of the bridge helix. Figure 1 shows the complete binding interactions of a–amanitin with the bridge helix region of RNAP. (13)
Figure 1 The deadly affects of the toxin a–amanitin from Amanita phalloides mushroom on the Rpb1 and 2 crevice and bridge helix regions of eukaryotic RNA polymerase. Bonding interactions inhibit the essential conformational changes in the bridge helix during transcriptional elongation. Rpb1 region corresponds to light green and Rpb2 bridge helix region to dark green, hydrogen bonds are represented by dashed lines. a–amanitin is represented by a dark line and corresponding numbers refer to a–Carbons. Figure from (Bushnell et al. 2002)
|
|
Jmol dervived images can give us a better look at this inhibbition.