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==Structure of the C. botulinum neurotoxin serotype A light chain protease in complex with covalent inhibitor 53==
<StructureSection load='6xce' size='340' side='right'caption='[[6xce]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XCE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UZM:(3S)-3-(2,4-dichlorophenyl)-N~1~-hydroxy-N~5~-(3-sulfanylpropyl)pentanediamide'>UZM</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6xce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xce OCA], [https://pdbe.org/6xce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xce RCSB], [https://www.ebi.ac.uk/pdbsum/6xce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xce ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Botulinum neurotoxins have remarkable persistence ( approximately 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(2+) 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 in vitro 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.

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.,Lin L, Olson ME, Sugane T, Turner LD, Tararina MA, Nielsen AL, Kurbanov EK, Pellett S, Johnson EA, Cohen SM, Allen KN, Janda KD J Med Chem. 2020 Sep 18. doi: 10.1021/acs.jmedchem.0c01006. PMID:32886509<ref>PMID:32886509</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Allen KN]]
[[Category: Tararina MA]]