Alpha amanitin is the most potent inhibitor of polymerase II. It is isolated from Amanita phalloides or the “death cap” mushroom and blocks both the initiation and elongation stages of transcription (1). The a-amanitin binds between the Rpb1 and Rpb 2 subunits across the cleft of pol II. Several hydrogen bonds between residues in the bridge helix and the a-amanitin are involved in the interaction. The binding of a-amanitin does not affect the binding affinity of ribonucleotides to the pol II complex, meaning that phophodiester bonds can still be formed. However, the rate of translocation, movement of the growing RNA strand, is reduced from several thousand to only a few ribonucleotides added per minute. This rate is slowed because of the inability of the bridge helix to move, due to the binding of a-amanitin, which is required for translocation.