View source for Acetylcholinesterase with DFP

<StructureSection load='2dfp'  size='350' side='right' scene='2dfp/Cv/1' caption="AChE complex with DFP [[2dfp]]">
[[Image:2dfp.png|left|200px]]

===X-RAY STRUCTURE OF AGED DI-ISOPROPYL-PHOSPHORO-FLUORIDATE (DFP) BOUND TO ACETYLCHOLINESTERASE===
(see also [[AChE inhibitors and substrates]], [[1cfj]], and [[1som]])

{{ABSTRACT_PUBMED_10353814}}
{{Clear}}
[[Acetylcholinesterase]] (AChE) [http://en.wikipedia.org/wiki/Hydrolysis hydrolysizes] the [http://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] <scene name='2wfz/Al/2'>acetylcholine (ACh)</scene>, producing <scene name='2wfz/Al/3'>choline and an acetate</scene> group. <scene name='2wfz/Al/2'>ACh</scene> directly binds [http://en.wikipedia.org/wiki/Catalysis catalytic] <scene name='2wfz/Al/4'>Ser200</scene> (via its [http://en.wikipedia.org/wiki/Nucleophile nucleophilic] Oγ atom). <scene name='2wfz/Al/5'>Soman</scene>, O-(1,2,2-trimethylpropyl) methylphosphonofluoridate (<font color='violet'><b>fluorine atom is colored violet</b></font> and <font color='darkmagenta'><b>phosphorus atom is colored darkmagenta</b></font>), is one of the most [http://en.wikipedia.org/wiki/Toxicity toxic] [http://en.wikipedia.org/wiki/Organophosphate organophosphate compounds (OPs)]. [http://en.wikipedia.org/wiki/Soman Soman] inhibits AChE by <scene name='2wfz/Al/6'>covalent binding</scene> to [http://en.wikipedia.org/wiki/Catalysis catalytic] Ser200, <scene name='2wfz/Al/7'>mimicking ACh</scene>. This process <scene name='2wfz/Al/8'>(phosphonylation)</scene> implicates [http://en.wikipedia.org/wiki/Nucleophile nucleophilic] attack of the Ser200 nucleophilic Oγ atom on the phosphorus atom of soman, with concomitant departure of its fluoride atom. After that AChE catalyzes the <scene name='2wfz/Al/9'>dealkylation ("aging")</scene> of the soman or other OP. This causes [http://en.wikipedia.org/wiki/Enzyme_inhibitor#Irreversible_inhibitors irreversible inhibition] of AChE, "aged" soman/AChE [http://en.wikipedia.org/wiki/Conjugated_system conjugate] can not be reactivated. However, before “aging”, at the step of <scene name='2wfz/Al/8'>phosphonylation</scene>, AChE can be <scene name='2wfz/Al/11'>reactivated</scene> by nucleophiles, such as [http://en.wikipedia.org/wiki/Pralidoxime pralidoxime] (2-PAM), resulting in <scene name='2wfz/Al/12'>cleavage</scene> of the phosphonyl adduct from Ser200 Oγ. 
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 <font color='yellow'><b>yellow</b></font>. 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 <font color='pink'><b>pink</b></font>. <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 [http://en.wikipedia.org/wiki/Imidazole 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]]).

{{Clear}}
DFP, di''iso''propylphosphorofluoridate, is an other toxic OP nerve agent. It is also inhibits AChE by covalent binding to the catalytic Ser200. There are four hydrogen bond donors (dotted lines) to the anionic phosphonyl oxygen atoms:  the backbone amide nitrogen atoms of Ala201, Gly118, and Gly119, as well as His440 Nε2 at the <scene name='2dfp/Cv/4'>active site</scene> of aged DFP-TcAChE ([[2dfp]]). Phosphorylation with DFP caused an unexpected distortion in the main chain of a loop that includes residues F288 and F290 of the TcAChE acyl binding pocket. F288 and F290 move significantly in the <font color='lime'><b>DFP-TcAChE structure (lime)</b></font>, in comparison to their positions in the <font color='magenta'><b>native enzyme</b></font> ([[2ace]]). This is the first major conformational change reported in the active site of any AChE−ligand complex, and it offers a structural explanation for the substrate selectivity of AChE.

==About this Structure==
[[2dfp|2DFP]] is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Torpedo_californica Torpedo californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DFP OCA]. 

==Additional Resources==
For additional information, see: [[Alzheimer's Disease]]
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</StructureSection>

==References==
<ref group="xtra">PMID:10353814</ref> <ref group="xtra">PMID:19642642</ref> <references group="xtra"/>
[[Category: Acetylcholinesterase]]
[[Category: Torpedo californica]]
[[Category: Kryger, G.]]
[[Category: Millard, C B.]]
[[Category: Silman, I.]]
[[Category: Sussman, J L.]]
[[Category: Aged organophosphate]]
[[Category: Alpha/beta hydrolase]]
[[Category: Catalytic triad]]
[[Category: Dfp]]
[[Category: Neurotransmitter cleavage]]
[[Category: Serine hydrolase]]
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Created with the participation of [[User:David Canner|David Canner]].