3DS9

A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate

Summary for 3DS9

• Entry DOI: 10.2210/pdb3ds9/pdb
• Related: 1XTF 2ISG 3DSE
• Descriptor: Botulinum neurotoxin type A, octapeptide I1 inhibitor, ZINC ION, ... (5 entities in total)
• Functional Keywords: snare, botulism, inhibition, metalloprotease, neurotransmission, neuromuscular junction, hydrolase, membrane, metal-binding, neurotoxin, pharmaceutical, protease, secreted, toxin, transmembrane, zinc
• Biological source: Clostridium botulinum
• Cellular location: Botulinum neurotoxin A light chain: Secreted. Botulinum neurotoxin A heavy chain: Secreted: A5HZZ9
• Total number of polymer chains: 2
• Total formula weight: 49032.34

Authors

Zuniga, J.E.,Fenn, T. (deposition date: 2008-07-11, release date: 2008-09-30, Last modification date: 2024-11-13)

Primary citation

Zuniga, J.E.,Schmidt, J.J.,Fenn, T.,Burnett, J.C.,Arac, D.,Gussio, R.,Stafford, R.G.,Badie, S.S.,Bavari, S.,Brunger, A.T.
A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate
Structure, 16:1588-1597, 2008

PubMed Abstract: 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 BoNT/A bound to a potent peptidomimetic inhibitor (K(i)=41 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 inhibitor's 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 BoNT/A as it does not inhibit other BoNT serotypes or thermolysin.

PubMed: 18940613
DOI: 10.1016/j.str.2008.07.011

Experimental method

X-RAY DIFFRACTION (1.758 Å)