A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A has a Very Different Conformation than SNAP-25 Substrate
HOWARD HUGHES MEDICAL INST CHEVY CHASE MD
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Botulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNTA bound to a potent peptidomimetic inhibitor Ki41 nM that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to the extended conformation of the native substrate. The backbone of the inhibitors P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the proton shuttle E224. This mechanism of inhibition is aided by residue contacts in the conserved S1 pocket of the substrate binding cleft and by the induction of new hydrophobic pockets, which are not present in the apo form, especially for the P2 residue of the inhibitor. Our inhibitor is specific for BoNTA as it does not inhibit other BoNT serotypes or thermolysin.