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6u37

From Proteopedia

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Structure of VX-phosphonylated hAChE in complex with oxime reactivator RS194B

Structural highlights

6u37 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.25Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are non-productive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE (hAChE), here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-hAChE conjugates. Oxime group re-orientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity.

Rational design, synthesis and evaluation of uncharged, "smart" bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase.,Gorecki L, Gerlits O, Kong X, Cheng X, Blumenthal DK, Taylor P, Ballatore C, Kovalevsky A, Radic Z J Biol Chem. 2020 Feb 4. pii: RA119.012400. doi: 10.1074/jbc.RA119.012400. PMID:32019865^[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
↑ Gorecki L, Gerlits O, Kong X, Cheng X, Blumenthal DK, Taylor P, Ballatore C, Kovalevsky A, Radic Z. Rational design, synthesis and evaluation of uncharged, "smart" bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase. J Biol Chem. 2020 Feb 4. pii: RA119.012400. doi: 10.1074/jbc.RA119.012400. PMID:32019865 doi:http://dx.doi.org/10.1074/jbc.RA119.012400

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6u37"

Categories: Homo sapiens | Large Structures | Gerlits O | Kovalevsky A | Radic Z

@@ Line 3: / Line 3: @@
 <StructureSection load='6u37' size='340' side='right'caption='[[6u37]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6u37]] 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=6U37 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6U37 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6u37]] 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=6U37 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U37 FirstGlance]. <br>
-</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=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=PQV:(2E)-N-[2-(azepan-1-yl)ethyl]-2-(hydroxyimino)acetamide'>PQV</scene>, <scene name='pdbligand=VX:O-ETHYLMETHYLPHOSPHONIC+ACID+ESTER+GROUP'>VX</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]] 2.25&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=PQV:(2E)-N-[2-(azepan-1-yl)ethyl]-2-(hydroxyimino)acetamide'>PQV</scene>, <scene name='pdbligand=VX:O-ETHYLMETHYLPHOSPHONIC+ACID+ESTER+GROUP'>VX</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6u37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u37 OCA], [https://pdbe.org/6u37 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u37 RCSB], [https://www.ebi.ac.uk/pdbsum/6u37 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u37 ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6u37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u37 OCA], [http://pdbe.org/6u37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u37 RCSB], [http://www.ebi.ac.uk/pdbsum/6u37 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u37 ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6u37" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Acetylcholinesterase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Gerlits, O]]
+[[Category: Gerlits O]]
-[[Category: Kovalevsky, A]]
+[[Category: Kovalevsky A]]
-[[Category: Radic, Z]]
+[[Category: Radic Z]]
-[[Category: Hydrolase]]
-[[Category: Oxime reactivator complex]]
-[[Category: Vx-phosphonylated conjugate]]

6u37

From Proteopedia

Current revision

Structure of VX-phosphonylated hAChE in complex with oxime reactivator RS194B

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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