7M1H
Crystal structure of LC/A-JPU-C10-JPU-D12-JPU-B8-JPU-G3-ciA-F12-ciA-D12
Summary for 7M1H
| Entry DOI | 10.2210/pdb7m1h/pdb |
| Descriptor | Botulinum neurotoxin A light chain, JPU-D12, ciA-F12, ... (9 entities in total) |
| Functional Keywords | vhh, protease domain, toxin, antitoxin |
| Biological source | Clostridium botulinum More |
| Total number of polymer chains | 7 |
| Total formula weight | 134059.06 |
| Authors | |
| Primary citation | Lam, K.H.,Tremblay, J.M.,Perry, K.,Ichtchenko, K.,Shoemaker, C.B.,Jin, R. Probing the structure and function of the protease domain of botulinum neurotoxins using single-domain antibodies. Plos Pathog., 18:e1010169-e1010169, 2022 Cited by PubMed Abstract: Botulinum neurotoxins (BoNTs) are among the deadliest of bacterial toxins. BoNT serotype A and B in particular pose the most serious threat to humans because of their high potency and persistence. To date, there is no effective treatment for late post-exposure therapy of botulism patients. Here, we aim to develop single-domain variable heavy-chain (VHH) antibodies targeting the protease domains (also known as the light chain, LC) of BoNT/A and BoNT/B as antidotes for post-intoxication treatments. Using a combination of X-ray crystallography and biochemical assays, we investigated the structures and inhibition mechanisms of a dozen unique VHHs that recognize four and three non-overlapping epitopes on the LC of BoNT/A and BoNT/B, respectively. We show that the VHHs that inhibit the LC activity occupy the extended substrate-recognition exosites or the cleavage pocket of LC/A or LC/B and thus block substrate binding. Notably, we identified several VHHs that recognize highly conserved epitopes across BoNT/A or BoNT/B subtypes, suggesting that these VHHs exhibit broad subtype efficacy. Further, we identify two novel conformations of the full-length LC/A, that could aid future development of inhibitors against BoNT/A. Our studies lay the foundation for structure-based engineering of protein- or peptide-based BoNT inhibitors with enhanced potencies and cross-subtypes properties. PubMed: 34990480DOI: 10.1371/journal.ppat.1010169 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.78 Å) |
Structure validation
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