6XCD

Structure of the C. botulinum neurotoxin serotype A light chain protease in complex with covalent inhibitor 22

Summary for 6XCD

• Entry DOI: 10.2210/pdb6xcd/pdb
• Descriptor: Botulinum neurotoxin type A, ZINC ION, N-hydroxy-7-sulfanylheptanamide, ... (4 entities in total)
• Functional Keywords: covalent inhibitor, hydroxamate, toxin, toxin-inhibitor complex, toxin/inhibitor
• Biological source: Clostridium botulinum
• Total number of polymer chains: 1
• Total formula weight: 50697.55

Authors

Tararina, M.A.,Allen, K.N. (deposition date: 2020-06-08, release date: 2021-06-09, Last modification date: 2024-10-23)

Primary citation

Lin, L.,Olson, M.E.,Sugane, T.,Turner, L.D.,Tararina, M.A.,Nielsen, A.L.,Kurbanov, E.K.,Pellett, S.,Johnson, E.A.,Cohen, S.M.,Allen, K.N.,Janda, K.D.
Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.
J.Med.Chem., 63:11100-11120, 2020

PubMed Abstract: Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.

PubMed: 32886509
DOI: 10.1021/acs.jmedchem.0c01006

Experimental method

X-RAY DIFFRACTION (1.92 Å)