Acetylcholinesterase

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<StructureSection load='ACHE2.pdb' size='400' side='right' scene='2ace/Ach/1' caption='Torpedo california AChE complex with acetylcholine (PDB code [[2ace]])'>
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<StructureSection load='' size='350' side='right' scene='22/22/Ache_with_ach/2' caption='Torpedo california AChE (PDB code [[2ace]])'>
[[Image:small_wh_ray0001.gif|left|150px]]<br />
[[Image:small_wh_ray0001.gif|left|150px]]<br />
'''Acetylcholinesterase''' (AChE) is key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, [[Acetylcholine|acetylcholine]] (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) poisons is attributed primarily to their potent AChE inhibitors.
'''Acetylcholinesterase''' (AChE) is key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, [[Acetylcholine|acetylcholine]] (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) poisons is attributed primarily to their potent AChE inhibitors.
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See also [[Acetylcholinesterase (Hebrew)]]
== Key Enzyme in the Nervous System ==
== Key Enzyme in the Nervous System ==
Solution of the three-dimensional (3D) structure of [http://en.wikipedia.org/wiki/Pacific_electric_ray ''Torpedo californica''] [[acetylcholinesterase]] (''Tc''AChE) in 1991 opened up new horizons in research on an [http://en.wikipedia.org/wiki/Enzyme enzyme] that had already been the subject of intensive investigation.<ref>PMID:1678899</ref> The unanticipated structure of this extremely rapid enzyme, in which the [http://en.wikipedia.org/wiki/Active_site active site] was found to be buried at the bottom of a <scene name='2ace/Active_site/3'>deep and narrow gorge</scene>, lined by <scene name='2ace/Active_site/4'>14 aromatic residues</scene> <font color='darkmagenta'><b>(colored dark magenta)</b></font>, led to a revision of the views then held concerning [http://en.wikipedia.org/wiki/Substrate_(biochemistry) substrate] traffic, recognition and hydrolysis.<ref>PMID:10545346</ref> To understand how those aromatic residues behave with the enzyme, see [[Flexibility of aromatic residues in acetylcholinesterase]]. Solution of the 3D structure of acetylcholinesterase led to a series of theoretical and experimental studies, which took advantage of recent advances in theoretical techniques for treatment of [http://en.wikipedia.org/wiki/Protein proteins], such as
Solution of the three-dimensional (3D) structure of [http://en.wikipedia.org/wiki/Pacific_electric_ray ''Torpedo californica''] [[acetylcholinesterase]] (''Tc''AChE) in 1991 opened up new horizons in research on an [http://en.wikipedia.org/wiki/Enzyme enzyme] that had already been the subject of intensive investigation.<ref>PMID:1678899</ref> The unanticipated structure of this extremely rapid enzyme, in which the [http://en.wikipedia.org/wiki/Active_site active site] was found to be buried at the bottom of a <scene name='2ace/Active_site/3'>deep and narrow gorge</scene>, lined by <scene name='2ace/Active_site/4'>14 aromatic residues</scene> <font color='darkmagenta'><b>(colored dark magenta)</b></font>, led to a revision of the views then held concerning [http://en.wikipedia.org/wiki/Substrate_(biochemistry) substrate] traffic, recognition and hydrolysis.<ref>PMID:10545346</ref> To understand how those aromatic residues behave with the enzyme, see [[Flexibility of aromatic residues in acetylcholinesterase]]. Solution of the 3D structure of acetylcholinesterase led to a series of theoretical and experimental studies, which took advantage of recent advances in theoretical techniques for treatment of [http://en.wikipedia.org/wiki/Protein proteins], such as
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[http://en.wikipedia.org/wiki/Molecular_dynamics molecular dynamics] and [http://en.wikipedia.org/wiki/Electrostatics electrostatics] and to [http://en.wikipedia.org/wiki/Site-directed_mutagenesis site-directed mutagenesis], utilizing suitable expression
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[http://en.wikipedia.org/wiki/Molecular_dynamics molecular dynamics] and [http://en.wikipedia.org/wiki/Electrostatics electrostatics] and to [http://en.wikipedia.org/wiki/Site-directed_mutagenesis site-directed mutagenesis], utilizing suitable expression systems.
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systems. [http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase] [http://en.wikipedia.org/wiki/Hydrolysis hydrolysizes] the [http://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] [http://en.wikipedia.org/wiki/Acetylcholine acetylcholine] <scene name='2ace/Cv/2'>(ACh)</scene>, producing <scene name='2ace/Cv/3'>choline and an acetate</scene> group. ACh directly binds <scene name='2ace/Cv/4'>Ser200</scene> (via its [http://en.wikipedia.org/wiki/Nucleophile nucleophilic] Oγ atom) within the <scene name='2ace/Cv/5'>catalytic triad (Ser200, His440, and Glu327)</scene> (ACh/''Tc''AChE structure [[2ace]]). The residues <scene name='2ace/Cv/6'>Trp84 and Phe330</scene> are also important in the [http://en.wikipedia.org/wiki/Ligand ligand] recognition <ref name="Raves">PMID:8989325</ref>. After this binding acetylcholinesterase <scene name='2ace/Cv/7'>hydrolysizes</scene> ACh. See also:<br />
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[[AChE inhibitors and substrates]]<br />
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[[Cholinesterase]]<br />
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[[Acetylcholinesterase (Hebrew)]]
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{{Clear}}
 
[[Image:Synapse_Schematic.jpg|thumb|Cholinergic Synapse|300px|left]]
[[Image:Synapse_Schematic.jpg|thumb|Cholinergic Synapse|300px|left]]
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{{Clear}}
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[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase] [http://en.wikipedia.org/wiki/Hydrolysis hydrolysizes] the [http://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] [http://en.wikipedia.org/wiki/Acetylcholine acetylcholine] <scene name='2ace/Cv/2'>(ACh)</scene>, producing <scene name='2ace/Cv/3'>choline and an acetate</scene> group. ACh directly binds <scene name='22/22/Cv/1'>Ser200</scene> (via its [http://en.wikipedia.org/wiki/Nucleophile nucleophilic] Oγ atom) within the <scene name='2ace/Cv/5'>catalytic triad (Ser200, His440, and Glu327)</scene> (ACh/''Tc''AChE structure [[2ace]]). The residues <scene name='2ace/Cv/6'>Trp84 and Phe330</scene> are also important in the [http://en.wikipedia.org/wiki/Ligand ligand] recognition <ref name="Raves">PMID:8989325</ref>. After this binding acetylcholinesterase <scene name='2ace/Cv/7'>hydrolysizes</scene> ACh. <br />
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See also [[Acetylcholinesterase with acetylcholine]].
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== Treatment of Alzheimer's disease ==
== Treatment of Alzheimer's disease ==
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[http://en.wikipedia.org/wiki/Alzheimer's_disease Alzheimer's disease] (AD) is a disorder that attacks the [http://en.wikipedia.org/wiki/Central_nervous_system central nervous system] through progressive degeneration of its neurons. AD occurs in around 10% of the elderly and, as yet, there is no known cure. Patients with this disease develop [http://en.wikipedia.org/wiki/Dementia dementia] which becomes more severe as the disease progresses. It was suggested that symptoms of AD are caused by decrease of activity of [http://en.wikipedia.org/wiki/Cholinergic cholinergic] [http://en.wikipedia.org/wiki/Neocortex neocortical] and [http://en.wikipedia.org/wiki/Hippocampus hippocampal] neurons. Treatment of AD by ACh precursors and [http://en.wikipedia.org/wiki/Cholinergic cholinergic] [http://en.wikipedia.org/wiki/Agonist agonists] was ineffective or caused severe side effects. ACh hydrolysis by AChE causes termination of cholinergic neurotransmission. Therefore, compounds which inhibit AChE might significantly increase the levels of ACh depleted in AD. Indeed, it was shown that [http://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor AChE inhibitors] improve the cognitive abilities of AD patients at early stages of the disease development.
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[http://en.wikipedia.org/wiki/Alzheimer's_disease Alzheimer's disease] (AD) is a disorder that attacks the [http://en.wikipedia.org/wiki/Central_nervous_system central nervous system] through progressive degeneration of its neurons. AD occurs in around 10% of the elderly and, as yet, there is no known cure. Patients with this disease develop [http://en.wikipedia.org/wiki/Dementia dementia] which becomes more severe as the disease progresses. It was suggested that symptoms of AD are caused by decrease of activity of [http://en.wikipedia.org/wiki/Cholinergic cholinergic] [http://en.wikipedia.org/wiki/Neocortex neocortical] and [http://en.wikipedia.org/wiki/Hippocampus hippocampal] neurons. Treatment of AD by ACh precursors and [http://en.wikipedia.org/wiki/Cholinergic cholinergic] [http://en.wikipedia.org/wiki/Agonist agonists] was ineffective or caused severe side effects. ACh hydrolysis by AChE causes termination of cholinergic neurotransmission. Therefore, compounds which inhibit AChE might significantly increase the levels of ACh depleted in AD. Indeed, it was shown that [http://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor AChE inhibitors] improve the cognitive abilities of AD patients at early stages of the disease development. The way in which the various cholinesterase inhibitors interact with AChE can be see at:<br />
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*[[Acetylcholinesterase: Treatment of Alzheimer's disease]].<br />
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=== The first generation of AD drugs - monovalent AChE inhibitors ===
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*[[Acetylcholinesterase complexed with N-9-(1',2',3',4'-tetrahydroacridinyl)-1,8-diaminooctane]].<br />
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The first generation of AD drugs were AChE inhibitors: alcaloids like [http://en.wikipedia.org/wiki/Huperzine_A (-)-Huperzine A (HupA)] and [http://en.wikipedia.org/wiki/Galantamine (-)-galanthamine (GAL, Reminyl)]; [http://en.wikipedia.org/wiki/Chemical_synthesis synthetic] compounds [http://en.wikipedia.org/wiki/Tacrine tacrine (Cognex)] and [http://en.wikipedia.org/wiki/Rivastigmine rivastigmine (Exelon)]. See also [[AChE bivalent inhibitors]]
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====HupA====
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'''HupA''', discovered by Chinese scientists from 1980s, has been proved to be a powerful, highly specific, and [http://en.wikipedia.org/wiki/Enzyme_inhibitor#Reversible_inhibitors reversible inhibitor] of AChE. The [http://en.wikipedia.org/wiki/X-ray_crystallography crystal structure] of the complex of ''Tc''AChE with HupA at 2.5 Å resolution ([[1vot]]) was determined in 1997 and it shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. <font color='blueviolet'><b>HupA</b></font> binds to ''Tc''AChE at the active site, and its <scene name='1vot/Active_site/8'>observed orientation is almost orthogonal</scene> in comparison to <font color='gray'><b>ACh</b></font>. The principal interactions of <scene name='1vot/1vot_ache_interactions/2'>HupA with TcAChE</scene> are including: a direct <scene name='1vot/1vot_199_130_117/2'>hydrogen bond with Tyr130 and HBs with Glu199 and Gly117 </scene> <span style="color:orange;background-color:black;font-weight:bold;">(colored orange)</span> through a water molecule as a linker at the bottom of the gorge; [http://en.wikipedia.org/wiki/Cation-pi_interaction cation-π] interactions between the amino group of <scene name='1vot/1vot_84_330/2'>HupA and Trp84 and Phe330</scene> <span style="color:lime;background-color:black;font-weight:bold;">(colored green)</span> with the distance between the nitrogen and the centroid of the aromatic rings of 4.8 and 4.7 Å, respectively; at the top of the gorge, [http://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] through two water molecules as linkers formed between the amino group of <scene name='1vot/1vot_70_72_81_85_121/3'>HupA and Tyr70, Asp72, Ser81, Asn85 and Tyr121</scene> <font color='magenta'><b>(colored magenta)</b></font>. An unusually short (~3.0 Å) C-H→O HB has been seen between the ethylidene methyl group of <scene name='1vot/1vot_440/2'>HupA and the main chain oxygen of His440</scene> <font color='crimson'><b>(colored crimson)</b></font> <ref name="Raves"/>.
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====Galanthamine====
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<scene name='AChE_inhibitors_and_substrates/Com_view_gal/1'>Galanthamine (GAL, Reminyl)</scene>. <scene name='AChE_inhibitors_and_substrates/Com_view_gal/2'>GAL</scene> <font color='red'><b>(red)</b></font> is an [http://en.wikipedia.org/wiki/Alkaloid alkaloid] from the flower snowdrop ([http://en.wikipedia.org/wiki/Galanthus ''Galanthus nivalis'']). The [http://en.wikipedia.org/wiki/X-ray_crystallography X-ray crystal structure] of the ''Tc''AChE/GAL complex ([[1dx6]]) was determined at 2.3 Å resolution. The inhibitor binds at the base of the [http://en.wikipedia.org/wiki/Active_site active site] gorge of ''Tc''AChE, interacting with both the choline-binding site (Trp84) and the acyl-binding pocket (Phe288, Phe290). The [http://en.wikipedia.org/wiki/Amine tertiary amine] appears to make a non-conventional [http://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bond], via its N-methyl group, to Asp72. The [http://en.wikipedia.org/wiki/Hydroxyl#Hydroxyl_group hydroxyl group] of the inhibitor makes a strong hydrogen bond (2.7 Å) with Glu199 <ref name="Greenblatt">PMID:10606746</ref>. <font color='gray'><b>ACh (gray)</b></font> is shown for comparison.
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====Tacrine====
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<scene name='AChE_inhibitors_and_substrates/Com_view_tacrine/1'>Tacrine</scene> ([[Cognex]]).
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In the X-ray crystal structure of ''Tc''AChE/<scene name='AChE_inhibitors_and_substrates/Com_view_tacrine/2'>tacrine</scene> complex which was determined at 2.8 Å resolution, the tacrine is seen <font color='magenta'><b>(magenta)</b></font> bound in the active site of ''Tc''AChE ([[1acj]]) <ref name="Harel">PMID:8415649</ref>. <font color='gray'><b>ACh (gray)</b></font> is shown for comparison.
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See [[Tacrine]].
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====Rivastigmine====
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<scene name='1gqr/Com_view/1'>Rivastigmine</scene> ([[Exelon]]) is a carbamate inhibitor of AChE, and it is currenly used in therapy of [[Alzheimer's Disease]]. <span style="color:yellow;background-color:black;font-weight:bold;">Rivastigmine (colored yellow)</span> interacts with ''Tc''AChE <span style="color:lime;background-color:black;font-weight:bold;">(colored green)</span> at the <scene name='1gqr/Active_site/4'>active-site gorge</scene> ([[1gqr]]). The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/9'>covalently bound</scene> to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, hence, carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE/<font color='magenta'><b>NAP (colored magenta)</b></font> is known ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are interacting with NAP are <font color='violet'><b>colored violet</b></font>. NAP is located in a similar region of ''Tc''AChE active site, but with different orientation than that of the <span style="color:yellow;background-color:black;font-weight:bold;">NAP part (colored yellow)</span> in the ''Tc''AChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap</scene> of the ''Tc''AChE active sites in 4 different structures <span style="color:lime;background-color:black;font-weight:bold;">''Tc''AChE</span>/rivastigmine ([[1gqr]]), <font color='violet'><b>''Tc''AChE</b></font>/<font color='magenta'><b>NAP</b></font> ([[1gqs]]), <span style="color:cyan;background-color:black;font-weight:bold;">native ''Tc''AChE</span> ([[2ace]]), and ''Tc''AChE/'''VX''' ([[1vxr]], ''Tc''AChE colored white and VX black) reveals that the conformation of H440 in the ''Tc''AChE/NAP structure is very similar its conformation in the native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly longer in the ''Tc''AChE/rivastigmine and the ''Tc''AChE/'''VX''' complexes. This structural change disrupts the [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by [[Rivastigmine]] <ref name="Bar-On">PMID:11888271</ref>.
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=== The second generation of AD drugs - bivalent AChE inhibitors ===
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The active site of <scene name='1zgb/Com_view/1'>TcAChE</scene> consists of <scene name='1zgb/Act_site/3'>two binding subsites</scene>. First of them is the "catalytic anionic site" ('''CAS'''), which involves mentioned above [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] <scene name='1zgb/Act_site/8'>Ser200, His440, and Glu327</scene> <span style="color:orange;background-color:black;font-weight:bold;">(colored orange)</span> and the [http://en.wikipedia.org/wiki/Conserved_sequence#Conserved_protein_sequences_and_Structures conserved residues] <scene name='1zgb/Act_site/5'>Trp84</scene> and <scene name='1zgb/Act_site/10'>Phe330</scene> also participating in ligands recognition. Another conserved residue <scene name='1zgb/Act_site/11'>Trp279</scene> <span style="color:cyan;background-color:black;font-weight:bold;">(colored cyan)</span> is situated at the second binding subsite, termed the "peripheral anionic site" ('''PAS'''), ~14 Å from '''CAS'''. Therefore, the ligands that will be able to interact with both these subsites, will be more potent [http://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor AChE inhibitors] in comparison to compounds interacting only with CAS (mentioned in the previous section "The first generation of AD drugs - monovalent AChE inhibitors"). One of the ways to produce such ligands is to introduce two active substances into one compound. If it is spatially necessary these subunits could be divided by alkyl linker with suitable length. For example, according to the strategy of the use of a bivalent ligand, the <scene name='1zgb/Comp/7'>inhibitor</scene> '''(''RS'')-(±)-tacrine-(10)-hupyridone''' ((R)-3 or (S)-3) was designed and synthesized. It consists of mentioned above <scene name='1zgb/Comp/8'>tacrine</scene> <font color='magenta'><b>(colored magenta)</b></font>, 10-carbon <scene name='1zgb/Comp/9'>linker</scene> <span style="color:yellow;background-color:black;font-weight:bold;">(yellow)</span>, and <scene name='1zgb/Comp/10'>hupyridone</scene> <font color='red'><b>(red)</b></font>. The tacrine moiety of this inhibitor binds at the CAS, the linker spans the <scene name='1zgb/Act_site/12'>active-site</scene> gorge, and the hupyridone moiety binds at the PAS ([[1zgb]]) <ref name="Haviv">PMID:16076210</ref>. There are also only PAS-binding AChE inhibitors, <scene name='2j3q/Active_site/6'>Thioflavin T</scene> <font color='magenta'><b>(magenta)</b></font> is a good example of them. <scene name='2j3q/Active_site/7'>Superposition</scene> of the crystal structure of the <font color='red'><b>edrophonium</b></font>/''Tc''AChE (CAS-binding inhibitor) ([[2ack]]) on the <font color='magenta'><b>thioflavin T</b></font>/''Tc''AChE complex structure ([[2j3q]]) shows that these ligands' positions do not overlap. Of note is that Phe330, which is part of the CAS, is the single residue interacting with <font color='magenta'><b>thioflavin T</b></font>. This residue is the only one which significantly <scene name='2j3q/Active_site/9'>changes its conformation</scene> to avoid clashes in comparison to other CAS residues of the <font color='red'><b>edrophonium</b></font>/''Tc''AChE complex <ref name="Ravelli">PMID:10089512</ref> <ref name="Sonoda">PMID:18512913</ref>.
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==== Galantamine ====
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Described above, <scene name='1w4l/Al/1'>Galantamine</scene> (abbreviated as <scene name='1w4l/Al/2'>GAL</scene>; <font color='red'><b>colored red</b></font>) is a CAS-binding inhibitor and it is currently used in therapy of [[Alzheimer's Disease]] under the trade name [[Razadyne]]. Conjugate of GAL through the <scene name='1w4l/Al/3'>alkyl linker</scene> (<span style="color:yellow;background-color:black;font-weight:bold;">8 carbons, yellow</span>) with a <scene name='1w4l/Al/4'>phthalimido moiety</scene> <font color='blueviolet'><b>(blueviolet)</b></font> called '''compound 3''' has a larger affinity for AChE than that of GAL alone. This is similar to previously described cases of bivalent ligands (''e.g.'' '''(''RS'')-)-tacrine-(10)-hupyridone'''). A comparison between <scene name='1w4l/Comparison/1'>compound 3</scene>/''Tc''AChE ([[1w4l]]) and <scene name='1w4l/Comparison/2'>galanthamine/TcAChE</scene> structure ([[1dx6]]) shows an identical binding mode of the <font color='red'><b>GAL-moiety (transparent red)</b></font> of '''compound 3''' to that of <font color='blue'><b>GAL alone (blue)</b></font> at the CAS. A <font color='gray'><b>PEG molecule (gray)</b></font> is located at the active site of the galanthamine/''Tc''AChE structure. The alkyl linker spans the active-site gorge and the phthalimido moiety of '''compound 3''' is situated near Trp279 at the PAS. '''Compound 3''' has higher affinity to ''Tc''AChE than GAL. This can be explained by the higher number of interactions between '''compound 3''' (which interacts not only with residues within CAS but also within PAS) and ''Tc''AChE relative to GAL <ref name="Guillou">PMID:15563167</ref>.
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====Aricept (donepezil, E2020)====
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<scene name='Main_Page/E2020_in_ache_spinning/1'>Aricept (E2020)</scene> ([[Donepezil]]) is one of the most interesting drugs that have been designed as AChE bivalent inhibitors. It was developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies prior to elucidation of the 3D structure of ''Torpedo californica'' AChE (''Tc''AChE) ([[1ea5]]). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. The X-ray structure of the E2020-''Tc''AChE complex ([[1eve]]) shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/13'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/7'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/5'>near W279</scene>), at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole' but only <scene name='1eve/E20_interactionshown/8'>indirectly via solvent molecules</scene>. The X-ray structure shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE, to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles <ref name="Kryger">PMID:10368299</ref>.<br />
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See [[Treatments:AChE Inhibitor References]].
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=====See details of AChE-Aricept complex in various languages=====
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[[1eve (German)]]<br />
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[[1eve (Hebrew)]]<br />
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[[1eve (Arabic)]]<br />
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[[1eve (Spanish)]]<br />
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[[1eve (Italian)]]<br />
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[[1eve (Chinese)]]<br />
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[[1eve (Turkish)]]<br />
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[[1eve (Russian)]]<br />
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== Organophosphorus acid anhydride nerve agents ==
== Organophosphorus acid anhydride nerve agents ==
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At the <scene name='2wfz/Ali/3'>active site of the nonaged soman/TcAChE conjugate</scene> ([[2wfz]]) the catalytic His440 forms hydrogen bonds with Ser200 Oγ and Glu327 Oε1 via its Nε2 and Nδ1 nitrogens, respectively. The O2 atom of soman is within hydrogen bonding distance of His440 Nε2. Soman O1 mimicks carbonyl oxygen of ACh. A water molecule 1001 interacting with soman O2 is represented as a <font color='red'><b>red ball</b></font>. The active site residues of the nonaged soman/TcAChE are colored <span style="color:yellow;background-color:black;font-weight:bold;">yellow</span>. The O2 atom of the <scene name='2wfz/Ali/4'>dealkylated (aged) soman</scene> ([[2wg0]]) forms a salt bridge with His440 Nε2. The active site residues of the aged soman/TcAChE are colored <span style="color:pink;background-color:black;font-weight:bold;">pink</span>. <scene name='2wfz/Ali/5'>Alignment</scene> of the structures of the nonaged ([[2wfz]]) and aged ([[2wg0]]) conjugates reveals a small, but important, change within the active site - the imidazole ring of His440 is tilted back to a native-like conformation after dealkylation. The water molecule 1001, which interacts with soman O2 in the nonaged crystal structure, is not within hydrogen bonding distance of O2 in the aged crystal structure. 2-PAM binds poorly to the nonaged phosphonylated enzyme (its electron density was not found) and binds in an <scene name='2wfz/Ali/7'>unfavorable and nonfunctional conformation</scene> after soman aging to ''Tc''AChE ([[2wg1]]) <ref name="Sanson">PMID:19642642</ref>.
At the <scene name='2wfz/Ali/3'>active site of the nonaged soman/TcAChE conjugate</scene> ([[2wfz]]) the catalytic His440 forms hydrogen bonds with Ser200 Oγ and Glu327 Oε1 via its Nε2 and Nδ1 nitrogens, respectively. The O2 atom of soman is within hydrogen bonding distance of His440 Nε2. Soman O1 mimicks carbonyl oxygen of ACh. A water molecule 1001 interacting with soman O2 is represented as a <font color='red'><b>red ball</b></font>. The active site residues of the nonaged soman/TcAChE are colored <span style="color:yellow;background-color:black;font-weight:bold;">yellow</span>. The O2 atom of the <scene name='2wfz/Ali/4'>dealkylated (aged) soman</scene> ([[2wg0]]) forms a salt bridge with His440 Nε2. The active site residues of the aged soman/TcAChE are colored <span style="color:pink;background-color:black;font-weight:bold;">pink</span>. <scene name='2wfz/Ali/5'>Alignment</scene> of the structures of the nonaged ([[2wfz]]) and aged ([[2wg0]]) conjugates reveals a small, but important, change within the active site - the imidazole ring of His440 is tilted back to a native-like conformation after dealkylation. The water molecule 1001, which interacts with soman O2 in the nonaged crystal structure, is not within hydrogen bonding distance of O2 in the aged crystal structure. 2-PAM binds poorly to the nonaged phosphonylated enzyme (its electron density was not found) and binds in an <scene name='2wfz/Ali/7'>unfavorable and nonfunctional conformation</scene> after soman aging to ''Tc''AChE ([[2wg1]]) <ref name="Sanson">PMID:19642642</ref>.
-
== Structural and functional characterization of the interaction of the photosensitizing probe methylene blue with ''Torpedo californica'' acetylcholinesterase <ref name="Paz">PMID:22674800</ref> ==
+
==Additional resources==
 +
see: [[Acetylcholinesterase_Additional_Resources]]
-
<hr/>
+
==Movies==
 +
see: [[Acetylcholinesterase_Movies]]
-
The photosensitizer, <scene name='Journal:Protein_Science:1/Cv/3'>methylene blue (MB)</scene> <font color='darkmagenta'><b>(colored in darkmagenta)</b></font>, generates singlet oxygen that irreversibly inhibits ''Torpedo californica'' acetylcholinesterase (''Tc''AChE). In the dark, it inhibits reversibly.
+
==Acetylcholinesterase 3D structures==
-
The ''Tc''AChE active site consists of two binding subsites. One of them is the '''"catalytic anionic site" (CAS)''', which involves the catalytic triad <scene name='Journal:Protein_Science:1/Cv/6'>Ser200, His440, and Glu327</scene> <span style="color:orange;background-color:black;font-weight:bold;">(colored in orange)</span> and the conserved residues <scene name='Journal:Protein_Science:1/Cv/8'>Trp84 and Phe330</scene> which also participate in ligand recognition. Another conserved residue <scene name='Journal:Protein_Science:1/Cv/9'>Trp279</scene> <span style="color:cyan;background-color:black;font-weight:bold;">(colored in cyan)</span> is situated at the second binding subsite, termed the '''"peripheral anionic site" (PAS)''', ~14 Å from CAS. <scene name='Journal:Protein_Science:1/Cv/10'>Thioflavin T</scene> ([[2j3q]]) is a good example of the '''PAS-binding''' AChE inhibitors. <scene name='Journal:Protein_Science:1/Cv/11'>Superposition</scene> of the structure of known '''CAS-binding''' inhibitor <font color='crimson'><b>edrophonium</b></font>/''Tc''AChE ([[2ack]]) on the <font color='magenta'><b>thioflavin T</b></font>/''Tc''AChE complex structure ([[2j3q]]) shows that these <scene name='Journal:Protein_Science:1/Cv/12'>ligands' positions do not overlap</scene> <ref name="Ravelli">PMID:10089512</ref> <ref name="Sonoda">PMID:18512913</ref>.
+
-
MB is a noncompetitive inhibitor of ''Tc''AChE, competing with reversible inhibitors directed at both ‘‘anionic’’ subsites, but a single site is involved in inhibition. The crystal structure reveals a <scene name='Journal:Protein_Science:1/Cv1/2'>single MB stacked against Trp279 in the PAS</scene>, oriented down the gorge toward the CAS ([[2w9i]]); it is plausible that irreversible inhibition is associated with photooxidation of this residue and others within the active-site gorge. Superposition of the '''PAS regions''' of the <font color='darkmagenta'><b>MB</b></font>/''Tc''AChE ([[2w9i]]) and <font color='magenta'><b>thioflavin T</b></font>/''Tc''AChE ([[2j3q]]) complexes reveals <scene name='Journal:Protein_Science:1/Cv1/4'>similarity between positions of these ligands</scene>. As the conformation of ''Tc''AChE in the crystal structures of the two complexes is practically identical, only that of the <font color='darkmagenta'><b>MB</b></font>/''Tc''AChE structure ([[2w9i]]) is shown. The kinetic and spectroscopic data showing that inhibitors binding at the '''CAS''' can impede binding of MB are reconciled by docking studies showing that the <scene name='Journal:Protein_Science:1/Cv2/5'>conformation adopted by Phe330</scene>, midway down the gorge, in the MB/''Tc''AChE crystal structure, precludes simultaneous binding of a second MB at the CAS (<font color='blueviolet'><b>2nd MB is colored blueviolet</b></font>, <span style="color:orange;background-color:black;font-weight:bold;">Phe330 of the crystal structure is in orange</span> and <font color='indigo'><b>Phe330 of the modeled structure is in indigo</b></font>). Conversely, binding of ligands at the '''CAS''' dislodges MB from its preferred locus at the '''PAS'''. The data presented demonstrate that TcAChE is a valuable model for understanding the molecular basis of local photooxidative damage.
+
-
For more details see<br />
+
[[Acetylcholinesterase 3D structures]]
-
*[[AChE bivalent inhibitors]] <br />
+
-
*[[Torpedo californica acetylcholinesterase with bifunctional inhibitor]]<br />
+
-
*[[Acetylcholinesterase: Substrate Traffic and Inhibition]]<br />
+
-
*[[Acetylcholinesterase Inhibitor Pharmacokinetics]]<br />
+
-
*[[Acetylcholinesterase inhibitors]]<br />
+
-
*[[AChE inhibitors and substrates]] <br />
+
-
*[[Human Acetylcholinesterase]]<br />
+
-
*[[African Malaria Mosquito Acetylcholinesterase]]<br />
+
-
*[[Acetylcholinesterase inhibited by nerve agent soman]]<br />
+
-
*[[Acetylcholinesterase with DFP]]<br />
+
-
*[[Acetylcholinesterase with OTMA]]<br />
+
-
*[[Acetylcholinesterase with acetylcholine]]<br />
+
-
*[[Acetylcholinesterase complexed with N-9-(1',2',3',4'-tetrahydroacridinyl)-1,8-diaminooctane]]<br />
+
-
*[[Complex of TcAChE with an iminium galanthamine derivative]]<br />
+
-
*[[Complex of TcAChE with bis-acting galanthamine derivative]]<br />
+
-
*[[Cholinesterase]]<br />
+
-
*[[Flexibility of aromatic residues in acetylcholinesterase]]<br />
+
-
*[[Huperzine A Complexed with Acetylcholinesterase]]<br />
+
-
*[[Torpedo Californica Acetylcholinesterase in complex with an (R)-Tacrine-(10)-Hupyridone inhibitor]]<br />
+
-
*[[Torpedo Californica Acetylcholinesterase in complex with an (S)-Tacrine-(10)-Hupyridone inhibitor]]<br />
+
-
*[[Torpedo californica acetylcholinesterase with alkylene-linked tacrine dimer (5 carbon linker)]]<br />
+
-
*[[Torpedo californica acetylcholinesterase with alkylene-linked tacrine dimer (7 carbon linker)]]<br />
+
-
*[[Torpedo californica acetylcholinesterase with bifunctional inhibitor]]<br />
+
-
*[[Tetramerization domain of acetylcholinesterase]]<br />
+
-
*[[Group:SMART:Acetylcholinesterase:A Story of Substrate Traffic and Inhibition by Green Mamba Snake Toxin]]<br />
+
-
See also a model of [[African Malaria Mosquito Acetylcholinesterase]].
+
==References==
 +
<references/>
</StructureSection>
</StructureSection>
- 
-
== 3D Structures of AChE ==
 
- 
-
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
 
-
{{#tree:id=OrganizedByTopic|openlevels=0|
 
- 
-
*Acetylcholinesterase - AChE native
 
- 
-
**[[3lii]], [[4ey4]] – hAChE - recombinant human <br />
 
-
**[[1ea5]], [[2ace]] – ''Tc''AChE – trigonal – ''Torpedo californica'' <br />
 
-
**[[2j3d]] – ''Tc''AChE – monoclinic <br />
 
-
**[[1w75]] – ''Tc''AChE – orthorhombic <br />
 
-
**[[2vt6]], [[2vt7]] – ''Tc''AChE – different dosage <br />
 
-
**[[1qid]] to [[1qim]] - ''Tc''AChE synchrotron radiation damage <br />
 
-
**[[1j06]], [[1maa]] – mAChE - mouse <br />
 
-
**[[1qo9]] – ''Dm''AChE - ''Drosophila melanogaster'' <br />
 
-
**[[1eea]], [[1c2b]], [[1c2o]] – AChE – Electric eel <br />
 
- 
-
*AChE inhibitors (In Different Languages)
 
- 
-
**[[1eve]] AChE-Aricept complex, [[1eve (Arabic)]], [[1eve (Chinese)]], [[1eve (Italian)]], [[1eve (Russian)]], [[1eve (Spanish)]], [[1eve (Turkish)]], [[1eve (Italian)]] <br />
 
-
**[[1vot]] AChE-Huperzine A complex, [[1vot (Chinese)]] <br />
 
- 
-
*AChE active site inhibitors conjugating at the bottom of the active site gorge
 
- 
-
**[[2c4h]] – ''Tc''AChE + acetylthiocholine<br />
 
-
**[[2w9i]] – ''Tc''AChE + methylene blue <br />
 
-
**[[2wls]] – MosAChE + AMTS13 <br />
 
-
**[[2vq6]] – ''Tc''AChE + 2-PAM <br />
 
-
**[[2j3q]] – ''Tc''AChE + Thioflavin T <br />
 
-
**[[2ha0]] – mAChE + ketoamyltrimethylammonium <br />
 
-
**[[2h9y]] – mAChE + TMTFA <br />
 
-
**[[3zlt]] – mAChE + RVX<br />
 
-
**[[3zlu]] – mAChE + cyclosarin<br />
 
-
**[[3zlv]] – mAChE + tabun + HI-6<br />
 
-
**[[4bc0]], [[4bc1]] – mAChE + CBDP<br />
 
-
**[[1gpk]], [[1gpn]], [[1vot]] – ''Tc''AChE + huperzine <br />
 
-
**[[4ey5]] – hAChE + huperzine<br />
 
-
**[[1gqr]] – ''Tc''AChE + rivastigmine <br />
 
-
**[[1gqs]] – ''Tc''AChE + NAP <br />
 
-
**[[1e66]] – ''Tc''AChE + huprine <br />
 
-
**[[4a16]] – mAChE + huprine <br />
 
-
**[[1dx4]], [[1qon]] – ''Dm''AChE + tacrine derivative <br />
 
-
**[[1oce]] – ''Tc''AChE + MF268 <br />
 
-
**[[1ax9]], [[1ack]] – ''Tc''AChE + edrophonium <br />
 
-
**[[1amn]] – ''Tc''AChE + TMTFA <br />
 
-
**[[1acj]] – ''Tc''AChE + tacrine <br />
 
-
**[[4tvk]] - TcAChE + tacrine hybrid<br />
 
-
**[[1u65]] – ''Tc''AChE + CPT-11<br />
 
-
**[[2bag]] - ''Tc''AChE + ganstigmine<br />
 
-
**[[2xi4]] - ''Tc''AChE + aflatoxin<br />
 
-
**[[4ara]], [[4arb]], [[4a23]], [[4b7z]], [[4b80]], [[4b81]], [[4b82]], [[4b83]], [[4b84]], [[4b85]], [[4btl]] - mAChE + inhibitor<br />
 
-
**[[2xuf]], [[2xug]], [[2xuh]], [[2xui]], [[2xuj]], [[2xuk]], [[2xuo]], [[2xup]], [[2xuq]] - mAChE (mutant) + inhibitor<br />
 
-
**[[4m0e]], [[4m0f]] - hAChE + inhibitor<br />
 
- 
-
*AChE peripheral site inhibitors conjugating at the surface of the protein
 
- 
-
**[[1ku6]], [[1mah]] - mAChE + fasciculin 2 <br />
 
-
**[[1j07]] - mAChE + decidium <br />
 
-
**[[1n5m]] - mAChE + gallamine <br />
 
-
**[[1n5r]] - mAChE + propidium <br />
 
-
**[[1b41]], [[1f8u]], [[4ey8]] - hAChE + fasciculin 2 <br />
 
-
**[[1fss]] - TcAChE + fasciculin 2 <br />
 
-
**[[2x8b]] - hAChE + fasciculin 2 + tabun<br />
 
-
**[[4bdt]] - hAChE + fasciculin 2 + huprine W<br />
 
- 
-
*AChE bis inhibitors spanning the active site gorge
 
- 
-
**[[3i6m]] – ''Tc''AChE + N-piperidinopropyl galanthamine <br />
 
-
**[[3i6z]] - ''Tc''AChE + saccharinohexyl galanthamine <br />
 
-
**[[1zgb]], [[1zgc]] – ''Tc''AChE + tacrine (10) hupyridone <br />
 
-
**[[2w6c]] – ''Tc''AChE + bis-(-)-nor-meptazinol <br />
 
-
**[[2ckm]], [[2cmf]] – ''Tc''AChE + bis-tacrine <br />
 
-
**[[2cek]] – ''Tc''AChE + N-[8-(1,2,3,4-tetrahydroacridin-9-ylthio)octyl]-1,2,3,4-tetrahydroacridin-9-amine <br />
 
-
**[[1ut6]] - ''Tc''AChE + N-9-(1,2,3,4-tetrahydroacridinyl)-1,8-diaminooctane <br />
 
-
**[[1odc]] - ''Tc''AChE + N-4-quinolyl-N-9-(1,2,3,4-tetrahydroacridinyl)-1,8-diaminooctane <br />
 
-
**[[1w4l]], [[1w6r]], [[1w76]], [[1dx6]], [[1qti]] - TcAChE + galanthamine and derivative <br />
 
-
**[[4ey6]] - hAChE + galanthamine<br />
 
-
**[[1q83]], [[1q84]] - mAChE + TZ2PA6 <br />
 
-
**[[1h22]], [[1h23]] – ''Tc''AChE + bis-hupyridone <br />
 
-
**[[1hbj]] – ''Tc''AChE + quinoline derivativev <br />
 
-
**[[1e3q]] – ''Tc''AChE + bw284c51 <br />
 
-
**[[1eve]] – ''Tc''AChE + e2020 <br />
 
-
**[[1acl]] – ''Tc''AChE + decamethonium <br />
 
-
**[[2xud]] – TcAChE (mutant) + decamethonium<br />
 
-
**[[3zv7]] - ''Tc''AChE + bisnorcymserine
 
- 
-
*AChE organophosphate inhibitors causing irreversible inhibition
 
- 
-
**[[2wu3]] – mAChE + fenamiphos and HI-6 <br />
 
-
**[[2wu4]] – mAChE + fenamiphos and ortho-7 <br />
 
-
**[[2jgf]] - mAChE + fenamiphos <br />
 
-
**[[2wfz]], [[2wg0]], [[2wg2]], [[1som]] - ''Tc''AChE + soman <br />
 
-
**[[2wg1]] - ''Tc''AChE + soman + 2-PAM <br />
 
-
**[[2whp]], [[2whq]], [[2whr]] – mAChE + sarin and HI-6 <br />
 
-
**[[2jgg]], [[2y2v]] - mAChE + sarin <br />
 
-
**[[2jgl]] - mAChE + VX and sarin <br />
 
-
**[[1cfj]] - ''Tc''AChE + sarin, GB <br />
 
-
**[[3dl4]], [[3dl7]] – mAChE + tabun <br />
 
-
**[[2jey]] – mAChE + HLO-7 <br />
 
-
**[[2c0p]], [[2c0q]] - mAChE + tabun <br />
 
-
**[[2jez]] - mAChE + tabun + HLO-7 <br />
 
-
**[[2jf0]] - mAChE + tabun + Ortho-7 <br />
 
-
**[[2jgh]], [[2y2u]] - mAChE + VX <br />
 
-
**[[1vxo]], [[1vxr]] - ''Tc''AChE + VX<br />
 
-
**[[2jgi]], [[2jgm]] - mAChE + DFP <br />
 
-
**[[1dfp]] - ''Tc''AChE + DFP <br />
 
-
**[[2jgj]], [[2jgk]], [[2jge]] - mAChE + methamidophos <br />
 
-
**[[2gyu]] - mAChE + HI-6 <br />
 
-
**[[2gyv]] - mAChE + Ortho-7 <br />
 
-
**[[2gyw]] - mAChE + obidoxime <br />
 
-
**[[3gel]] - TcAChE + methyl paraoxon<br />
 
-
**[[2dfp]] – TcAChE aged<br />
 
- 
-
*AChE substrate analogues mimicking the binding of the substrate acetylcholine
 
- 
-
**[[2ha4]] – mAChE (mutant) + acetylcholine <br />
 
-
**[[2vja]], [[2vjb]], [[2vjc]], [[2vjd]], [[2cf5]] – TcAChE + 4-oxo-N,N,N-trimethylpentanaminium
 
-
**[[2v96]], [[2v97]], [[2v98]], [[2v99]] – ''Tc''AChE + 1-(2-nitrophenyl)-2,2,2-trifluoroethyl-arsenocholine <br />
 
-
**[[2ha2]] – mAChE + succinylcholine <br />
 
-
**[[2ha3]] - mAChE + choline <br />
 
-
**[[2ha5]] – mAChE (mutant) + acetylthiocholine <br />
 
-
**[[2ha6]] – mAChE (mutant) + succinylthiocholine <br />
 
-
**[[2ha7]] – mAChE (mutant) + butyrylthiocholine <br />
 
-
**[[2ch4]], [[2c58]] – ''Tc''AChE + acetylthiocholine <br />
 
-
**[[2c5g]] – ''Tc''AChE + thiocholine <br />
 
-
**[[2c5f]] – TcAChE + substrate analog<br />
 
-
**[[2va9]] - TcAChE + ‘caged’ arsenocholine<br />
 
-
**[[4ey7]] – hAChE + donepezil<br />
 
- 
-
*Others...
 
- 
-
**[[2j4f]] – ''Tc''AChE + Hg <br />
 
-
**[[1vzj]] – ''Tc''AChE tetramerization domain <br />
 
-
**[[1jjb]] – ''Tc''AChE + PEG <br />
 
-
**[[1qie]], [[1qif]], [[1qig]], [[1qih]], [[1qii]], [[1qij]], [[1qik]] – TcAChE synchrotron radiation damage <br />
 
-
**[[3m3d]] – TcAChE + Xe<br />
 
-
**[[4qww]] – AChE + antibody – banded krait<br />
 
-
}}
 
- 
-
==Additional Resources==
 
-
For additional information, see:<br />
 
-
[[Alzheimer's Disease]]<br />
 
-
[[AChE inhibitors and substrates]]<br />
 
- 
- 
[[Category: catalytic triad]]
[[Category: catalytic triad]]
[[Category: cholinesterase]]
[[Category: cholinesterase]]
-
[[Category: cholinesterases]]
 
[[Category: acetylcholine]]
[[Category: acetylcholine]]
[[Category: cation-pi]]
[[Category: cation-pi]]
Line 266: Line 48:
[[Category: nerve gasses]]
[[Category: nerve gasses]]
-
==External Links ==
 
-
*[http://www.messiah.edu/departments/chemistry/molscilab/jtat_080120/acetylcholinesterase/contents/contents.htm Acetylcholinesterase Tutorial] by Karl Oberholser, Messiah College
 
-
*[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb54_1.html PDB Molecule of the Month - Acetylcholinesterase]
 
-
*[http://www.weizmann.ac.il/sb/faculty_pages/Sussman/movies/Radiation_Damage Movies: X-ray Damage in ACh] & [http://www.weizmann.ac.il/sb/faculty_pages/Sussman/movies/richardnew.mpg Nature's Vacuum Cleaner] by R. Gillilan, Cornell Univ
 
-
==References==
 
- 
-
<references/>
 
-
[[Treatments:AChE Inhibitor References]]<br />
 
-
[[Treatments:Alzheimer's Disease]]
 
-
[[he:Acetylcholinesterase_(Hebrew)]]
 
[[Category:Topic Page]]
[[Category:Topic Page]]

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Torpedo california AChE (PDB code 2ace)

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