|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6o66' size='340' side='right'caption='[[6o66]], [[Resolution|resolution]] 2.45Å' scene=''> | | <StructureSection load='6o66' size='340' side='right'caption='[[6o66]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6o66]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O66 FirstGlance]. <br> | + | <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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.452Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SVX:O-[(R)-ETHOXY(METHYL)PHOSPHORYL]-L-SERINE'>SVX</scene></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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6o5r|6o5r]], [[6o5s|6o5s]], [[6o5v|6o5v]]</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> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACHE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o66 OCA], [http://pdbe.org/6o66 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o66 RCSB], [http://www.ebi.ac.uk/pdbsum/6o66 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o66 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 26: |
Line 23: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Acetylcholinesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gerlits, O]] | + | [[Category: Gerlits O]] |
| - | [[Category: Kovalevsky, A]] | + | [[Category: Kovalevsky A]] |
| - | [[Category: Radic, Z]] | + | [[Category: Radic Z]] |
| - | [[Category: Human acetylcholinesterase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Imidazole-based oxime]]
| + | |
| - | [[Category: Oxime reactivator]]
| + | |
| - | [[Category: Rs-170b]]
| + | |
| - | [[Category: Vx-hache]]
| + | |
| - | [[Category: Vx-phosphonylated]]
| + | |
| Structural highlights
Function
ACES_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 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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chhajlani V, Derr D, Earles B, Schmell E, August T. Purification and partial amino acid sequence analysis of human erythrocyte acetylcholinesterase. FEBS Lett. 1989 Apr 24;247(2):279-82. PMID:2714437
- ↑ Velan B, Grosfeld H, Kronman C, Leitner M, Gozes Y, Lazar A, Flashner Y, Marcus D, Cohen S, Shafferman A. The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant. J Biol Chem. 1991 Dec 15;266(35):23977-84. PMID:1748670
- ↑ Shafferman A, Kronman C, Flashner Y, Leitner M, Grosfeld H, Ordentlich A, Gozes Y, Cohen S, Ariel N, Barak D, et al.. Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. J Biol Chem. 1992 Sep 5;267(25):17640-8. PMID:1517212
- ↑ Yang L, He HY, Zhang XJ. Increased expression of intranuclear AChE involved in apoptosis of SK-N-SH cells. Neurosci Res. 2002 Apr;42(4):261-8. PMID:11985878
- ↑ Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radic Z, Kovalevsky A. Productive reorientation of a bound oxime reactivator revealed in room-temperature X-ray structures of native and VX-inhibited human acetylcholinesterase. J Biol Chem. 2019 May 28. pii: RA119.008725. doi: 10.1074/jbc.RA119.008725. PMID:31138650 doi:http://dx.doi.org/10.1074/jbc.RA119.008725
|
