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1b41
From Proteopedia
Contents |
Human Acetylcholinesterase (1b41)
| 1b41, resolution 2.76Å () | |||||||||
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| Sites: | , , and | ||||||||
| Ligands: | , , | ||||||||
| Gene: | ACHE (Homo sapiens) | ||||||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
The human acetylcholinesterase (AChE) is an enzyme which hydrolyses the neurotransmitter Acethylcholin (ACh) in the neuromuscular junctions and in other cholinergic synapses to terminate the neuronal signal. It has an ellipsoidal shape with dimensions ~ 4,5nm x 6nm x 6,5nm. This protein is composed of 531 residues. It consists of 12-stranded, central mixed surrounded by 14 .
In the physiological conditions, AChE exists as tetramers associated with either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein (PRiMA). The AChE is linked with these anchoring molecules by a "tryptophan amphiphilic tetramerization" domain (WAT). There is also a monomeric form which is soluble in the blood.
The Active site gorge of AChE
The active site of AChE involves two sites: the peripheral site and the catalytic site.
The peripheral site is a transitional binding site of the substrate. It provides a region rich in aromatic amino acids that guide the ligands (ACh or other agonists) by setting an array of low-affinity binding sites. This hydrophobic region traps ACh and transfers it to the deep catalytic site.
The catalytic site of AChE consists of two subsites: the "esteratic" site and "the anionic" site.
In the "esteratic site" a catalytic triad consisting of forms a planar array that resembles the catalytic triad of serine proteases. S203 is activated (it becomes nucleophilic) by E334 and H447. This activation allows the following reaction: the acylation between hydroxyl group of S203 and ACh oxygen (or other agonists). A covalent bond between the enzyme and the substrate creates an oxyanion. This oxyanion then reacts with two glycins setting up a hydrogen bond. In the "anionic" site, the binds trimethylammonium group of ACh.
Further to these steps the substrate is well positioned to be hydrolysed into acetic acid and cholin.
Inhibitors of AChE
Fasciculin II
Fasciculin is a snake toxin. It is a little protein of 7kDa which inhibits AChE in binding the peripheric site, preventing the substrate from passing through the narrower portion of the gorge towards the catalytic site. This inhibition is almost irreversible. The toxin is the one used in cristallisation of the Human acetylcholinesterase (in green on the picture).
Inhibitors used as treatments
We can find a lot of inhibitors such as in Alzheimer's disease drugs treatment. Actually, Alzheimer's disease is a neurodegenerative disease in which ACh is less present. An inhibition approach can be used to increase the remaining of ACh in the synaptic cleft by inhibiting the action of AChE. These treatments include rivastigmine, donepezil and tacrine. However, these drugs do not cure this disease, but only delay its development.
The molecule which has been the most studied is tacrine. A monomer of tacrine binds strongly to the peripheral site, preventing the subtrate from entry. When tacrine is in the dimer shape, it can bind the catalytic and peripheral sites of AChE.
References, for further information on Acetylcholinesterase
To the structures used here:
- Li W, Mak M, Jiang H, Wang Q, Pang Y, Chen K & Han Y (2009) "Novel anti-Alzheimer's dimer Bis(7)-cognitin: cellular and molecular mechanisms of neuroprotection through multiple targets", Neurotherapeutics, vol.6, p.187-201.
- Zhang D & McCammon JA (2005) "The association of tetrameric acetylcholinesterase with colQ tail: a block normal mode analysis", PLoS Comput Biology, vol.1, p.484-491.
To the active site of acetylcholinesterase
- Rosenberry TL (2009) "Strategies to resolve the catalytic mechanism of acetylcholinesterase", Journal of Molecular Neuroscience.
- Currently (November 05, 2009), part of the content of this page is inspired from a source: http://www.biochimie.univ-montp2.fr/licence/enzymo/ache/ache.htm
Hélène ERASIMUS, Blandine FAUVEL, Tiphaine Jaeg 17:08, 12 November 2009 (IST)
| 1b41, resolution 2.76Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Sites: | , , and | ||||||||
| Ligands: | , , | ||||||||
| Gene: | ACHE (Homo sapiens) | ||||||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||||||
| |||||||||
| |||||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
HUMAN ACETYLCHOLINESTERASE COMPLEXED WITH FASCICULIN-II, GLYCOSYLATED PROTEIN
Structures of recombinant wild-type human acetylcholinesterase and of its E202Q mutant as complexes with fasciculin-II, a 'three-finger' polypeptide toxin purified from the venom of the eastern green mamba (Dendroaspis angusticeps), are reported. The structure of the complex of the wild-type enzyme was solved to 2.8 A resolution by molecular replacement starting from the structure of the complex of Torpedo californica acetylcholinesterase with fasciculin-II and verified by starting from a similar complex with mouse acetylcholinesterase. The overall structure is surprisingly similar to that of the T. californica enzyme with fasciculin-II and, as expected, to that of the mouse acetylcholinesterase complex. The structure of the E202Q mutant complex was refined starting from the corresponding wild-type human acetylcholinesterase structure, using the 2.7 A resolution data set collected. Comparison of the two structures shows that removal of the charged group from the protein core and its substitution by a neutral isosteric moiety does not disrupt the functional architecture of the active centre. One of the elements of this architecture is thought to be a hydrogen-bond network including residues Glu202, Glu450, Tyr133 and two bridging molecules of water, which is conserved in other vertebrate acetylcholinesterases as well as in the human enzyme. The present findings are consistent with the notion that the main role of this network is the proper positioning of the Glu202 carboxylate relative to the catalytic triad, thus defining its functional role in the interaction of acetylcholinesterase with substrates and inhibitors.
Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II., Kryger G, Harel M, Giles K, Toker L, Velan B, Lazar A, Kronman C, Barak D, Ariel N, Shafferman A, Silman I, Sussman JL, Acta Crystallogr D Biol Crystallogr. 2000 Nov;56(Pt 11):1385-94. PMID:11053835
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Disease
Known disease associated with this structure: Blood group, Yt system OMIM:[100740]
About this Structure
1B41 is a 2 chains structure with sequences from Dendroaspis angusticeps and Homo sapiens. The June 2004 RCSB PDB Molecule of the Month feature on Acetylcholinesterase by David S. Goodsell is 10.2210/rcsb_pdb/mom_2004_6. Full crystallographic information is available from OCA.
Reference
- Kryger G, Harel M, Giles K, Toker L, Velan B, Lazar A, Kronman C, Barak D, Ariel N, Shafferman A, Silman I, Sussman JL. Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr D Biol Crystallogr. 2000 Nov;56(Pt 11):1385-94. PMID:11053835
Page seeded by OCA on Thu Jan 21 09:34:52 2010
