8dt5: Difference between revisions
m Protected "8dt5" [edit=sysop:move=sysop] |
No edit summary |
||
| Line 1: | Line 1: | ||
==X-ray structure of human acetylcholinesterase ternary complex with paraoxon and oxime RS170B (POX-hAChE-RS170B)== | |||
<StructureSection load='8dt5' size='340' side='right'caption='[[8dt5]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8dt5]] 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=8DT5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DT5 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DEP:DIETHYL+PHOSPHONATE'>DEP</scene>, <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></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=8dt5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dt5 OCA], [https://pdbe.org/8dt5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dt5 RCSB], [https://www.ebi.ac.uk/pdbsum/8dt5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dt5 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 == | |||
Organophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime antidotes can reactivate the OP-conjugated hAChE, but reactivation efficiency can be low for pesticides, such as paraoxon (POX). Understanding structural and dynamic determinants of OP inhibition and reactivation can provide insights to design improved reactivators. Here, X-ray structures of hAChE with unaged POX, with POX and oximes MMB4 and RS170B, and with MMB4 are reported. A significant conformational distortion of the acyl loop was observed upon POX binding, being partially restored to the native conformation by oximes. Neutron vibrational spectroscopy combined with molecular dynamics simulations showed that picosecond vibrational dynamics of the acyl loop soften in the approximately 20-50 cm(-1) frequency range. The acyl loop structural perturbations may be correlated with its picosecond vibrational dynamics to yield more comprehensive template for structure-based reactivator design. | |||
Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering.,Gerlits O, Fajer M, Cheng X, Blumenthal DK, Radic Z, Kovalevsky A Structure. 2022 Oct 12. pii: S0969-2126(22)00373-2. doi:, 10.1016/j.str.2022.09.006. PMID:36265484<ref>PMID:36265484</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8dt5" style="background-color:#fffaf0;"></div> | ||
[[Category: Kovalevsky | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gerlits O]] | |||
[[Category: Kovalevsky AY]] | |||
[[Category: Radic Z]] | |||
Revision as of 10:25, 3 November 2022
X-ray structure of human acetylcholinesterase ternary complex with paraoxon and oxime RS170B (POX-hAChE-RS170B)X-ray structure of human acetylcholinesterase ternary complex with paraoxon and oxime RS170B (POX-hAChE-RS170B)
Structural highlights
FunctionACES_HUMAN Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.[1] [2] [3] [4] Publication Abstract from PubMedOrganophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime antidotes can reactivate the OP-conjugated hAChE, but reactivation efficiency can be low for pesticides, such as paraoxon (POX). Understanding structural and dynamic determinants of OP inhibition and reactivation can provide insights to design improved reactivators. Here, X-ray structures of hAChE with unaged POX, with POX and oximes MMB4 and RS170B, and with MMB4 are reported. A significant conformational distortion of the acyl loop was observed upon POX binding, being partially restored to the native conformation by oximes. Neutron vibrational spectroscopy combined with molecular dynamics simulations showed that picosecond vibrational dynamics of the acyl loop soften in the approximately 20-50 cm(-1) frequency range. The acyl loop structural perturbations may be correlated with its picosecond vibrational dynamics to yield more comprehensive template for structure-based reactivator design. Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering.,Gerlits O, Fajer M, Cheng X, Blumenthal DK, Radic Z, Kovalevsky A Structure. 2022 Oct 12. pii: S0969-2126(22)00373-2. doi:, 10.1016/j.str.2022.09.006. PMID:36265484[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||