3QW6: Crystal Structure Of The Protease Domain Of Botulinum Neurotoxin Serotype A With A Peptide Inhibitor Rygc

Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC(50) of 0.9 microM and a K(i) of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.
PDB ID: 3QW6Download
MMDB ID: 103121
PDB Deposition Date: 2011/2/26
Updated in MMDB: 2012/09
Experimental Method:
x-ray diffraction
Resolution: 1.6  Å
Source Organism:
Clostridium botulinum A str. Hall
Similar Structures:
Biological Unit for 3QW6: dimeric; determined by author and by software (PISA)
Molecular Components in 3QW6
Label Count Molecule
Proteins (2 molecules)
Botulinum Neurotoxin Type a(Gene symbol: atx)
Molecule annotation
Inhibitory Peptide Rygc
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB