View source for 6o66


==Structure of VX-phosphonylated hAChE in complex with oxime reactivator RS-170B==
<StructureSection load='6o66' size='340' side='right'caption='[[6o66]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6o66]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O66 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]] 2.452&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LND:4-carbamoyl-1-(3-{2-[(E)-(hydroxyimino)methyl]-1H-imidazol-1-yl}propyl)pyridin-1-ium'>LND</scene>, <scene name='pdbligand=SVX:O-[(R)-ETHOXY(METHYL)PHOSPHORYL]-L-SERINE'>SVX</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=6o66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o66 OCA], [https://pdbe.org/6o66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o66 RCSB], [https://www.ebi.ac.uk/pdbsum/6o66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o66 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ACES_HUMAN ACES_HUMAN] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.<ref>PMID:2714437</ref> <ref>PMID:1748670</ref> <ref>PMID:1517212</ref> <ref>PMID:11985878</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a 'non-productive' pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a 'semi-productive' orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient while being bound inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation OP antidotes.

Productive reorientation of a bound oxime reactivator revealed in room-temperature X-ray structures of native and VX-inhibited human acetylcholinesterase.,Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radic Z, Kovalevsky A J Biol Chem. 2019 May 28. pii: RA119.008725. doi: 10.1074/jbc.RA119.008725. PMID:31138650<ref>PMID:31138650</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6o66" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gerlits O]]
[[Category: Kovalevsky A]]
[[Category: Radic Z]]