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| | ==Crystal structure of the Fab410-BfAChE complex== | | ==Crystal structure of the Fab410-BfAChE complex== |
| - | <StructureSection load='4qww' size='340' side='right' caption='[[4qww]], [[Resolution|resolution]] 2.70Å' scene=''> | + | <StructureSection load='4qww' size='340' side='right'caption='[[4qww]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qww]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Bungarus_fasciatus Bungarus fasciatus] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QWW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QWW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qww]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bungarus_fasciatus Bungarus fasciatus] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QWW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4qww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qww OCA], [https://pdbe.org/4qww PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qww RCSB], [https://www.ebi.ac.uk/pdbsum/4qww PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qww ProSAT]</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=4qww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qww OCA], [http://pdbe.org/4qww PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qww RCSB], [http://www.ebi.ac.uk/pdbsum/4qww PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qww ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACES_BUNFA ACES_BUNFA]] In muscle, it terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. In liver, its function is unclear: it could serve as a safeguard against any diffusion of acetylcholine from synapses into the circulation. In venom, its toxic role is unclear: It could result in less musculatory control by rapidly hydrolyzing acetylcholine, or that it works synergistically with alkaline phosphatase (ALP) in paralyzing prey through hypotension. | + | [https://www.uniprot.org/uniprot/ACES_BUNFA ACES_BUNFA] In muscle, it terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. In liver, its function is unclear: it could serve as a safeguard against any diffusion of acetylcholine from synapses into the circulation. In venom, its toxic role is unclear: It could result in less musculatory control by rapidly hydrolyzing acetylcholine, or that it works synergistically with alkaline phosphatase (ALP) in paralyzing prey through hypotension. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | *[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] | | *[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] |
| - | *[[3D structures of acetylcholinesterase|3D structures of acetylcholinesterase]] | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| - | *[[3D structures of antibody|3D structures of antibody]] | + | *[[3D structures of non-human antibody|3D structures of non-human antibody]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Acetylcholinesterase]] | |
| | [[Category: Bungarus fasciatus]] | | [[Category: Bungarus fasciatus]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Bourne, Y]] | + | [[Category: Bourne Y]] |
| - | [[Category: Marchot, P]] | + | [[Category: Marchot P]] |
| - | [[Category: Renault, L]] | + | [[Category: Renault L]] |
| - | [[Category: A/b hydrolase fold]]
| + | |
| - | [[Category: Hydrolase-immune system complex]]
| + | |
| - | [[Category: Monoclonal antibody]]
| + | |
| Structural highlights
Function
ACES_BUNFA In muscle, it terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. In liver, its function is unclear: it could serve as a safeguard against any diffusion of acetylcholine from synapses into the circulation. In venom, its toxic role is unclear: It could result in less musculatory control by rapidly hydrolyzing acetylcholine, or that it works synergistically with alkaline phosphatase (ALP) in paralyzing prey through hypotension.
Publication Abstract from PubMed
The acetylcholinesterase found in the venom of Bungarus fasciatus (BfAChE) is produced as a soluble, non-amphiphilic monomer with a canonical catalytic domain but a distinct C-terminus compared to the other vertebrate enzymes. Moreover, the peripheral anionic site of BfAChE, a surface site located at the active-site gorge entrance, bears two substitutions altering sensitivity to cationic inhibitors. Antibody Elec410, generated against Electrophorus electricus acetylcholinesterase (EeAChE), inhibits EeAChE and BfAChE by binding to their peripheral sites. Yet both complexes retain significant residual catalytic activity, suggesting incomplete gorge occlusion by bound antibody and/or high-frequency backdoor opening. To explore a novel acetylcholinesterase species, ascertain the molecular bases of inhibition by Elec410, and document the determinants and mechanisms for backdoor opening, we solved a 2.7A-resolution crystal structure of natural BfAChE in complex with antibody fragment Fab410. Crystalline BfAChE forms the canonical dimer found in all acetylcholinesterase structures. Equally represented open and closed states of a backdoor channel, associated with alternate positions of a tyrosine phenol ring at the active site base, coexist in each subunit. At the BfAChE molecular surface, Fab410 is seated on the long Omega-loop between two N-glycan chains and partially occludes the gorge entrance, a position that fully reflects the available mutagenesis and biochemical data. Experimentally based flexible molecular docking supports a similar Fab410 binding mode onto the EeAChE antigen. These data document the molecular and dynamic peculiarities of BfAChE with high-frequency backdoor opening, and the mode of action of Elec410 as one of the largest peptidic inhibitors targeting the acetylcholinesterase peripheral site.
Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 bound at the Peripheral Site: Evidence for Open and Closed States of a Backdoor Channel.,Bourne Y, Renault L, Marchot P J Biol Chem. 2014 Nov 19. pii: jbc.M114.603902. PMID:25411244[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bourne Y, Renault L, Marchot P. Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 bound at the Peripheral Site: Evidence for Open and Closed States of a Backdoor Channel. J Biol Chem. 2014 Nov 19. pii: jbc.M114.603902. PMID:25411244 doi:http://dx.doi.org/10.1074/jbc.M114.603902
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