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1ea5
From Proteopedia
| 1ea5, resolution 1.80Å () | |||||||||
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| Sites: | and | ||||||||
| Ligands: | |||||||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||||||
| Related: | 1amn, 1ax9, 1cfj, 1dx6, 1e3q, 1e66, 1eea, 1eve, 1fss, 1oce, 1qid, 1qie, 1qif, 1qig, 1qih, 1qii, 1qij, 1qik, 1qim, 1qti, 1som, 1vot, 1vxo, 1vxr, 2ace, 2ack, 2dfp, 3ace | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Acetylcholinesterase (E.C. 3.1.1.7)
Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 microM, respectively, compared to 0.18 microM for (-)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to 2.1 and 2.35 A resolution, respectively, and compared to the previously determined structure of the (-)-huperzine A complex. All three interact with the "anionic" subsite of the active site, primarily through pi-pi stacking and through van der Waals or C-H.pi interactions with Trp84 and Phe330. Since their alpha-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H.pi interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the "oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged "oxyanion hole" characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charged or neutral.
X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement., Dvir H, Jiang HL, Wong DM, Harel M, Chetrit M, He XC, Jin GY, Yu GL, Tang XC, Silman I, Bai DL, Sussman JL, Biochemistry. 2002 Sep 3;41(35):10810-8. PMID:12196020
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Contents |
Overview
The 3D structure of acetylcholinesterase (AChE) from Torpedo californica electric organ has been determined by x-ray analysis to 1.8 Å resolution. The form crystallized is the glycolipid-anchored homodimer that was purified subsequent to solubilization with a bacterial phosphatidylinositol-specific phospholipase C. The enzyme monomer is an α/β structure protein that contains 537 amino acids. It consists of a 12-stranded mixed beta sheet surrounded by 14 α-helices and bears a striking resemblance to several hydrolase structures including dienelactone hydrolase, serine carboxypeptidase-II, three neutral lipases, and haloalkane dehalogenase. The is unusual because it contains Glu, not Asp, in the Ser-His-acid catalytic triad and because the relation of the triad to the rest of the protein approximates a mirror image of that seen in the serine proteases. Furthermore, the active site lies near the bottom of a deep and narrow gorge that reaches halfway into the protein. Modeling of acetylcholine binding to the enzyme suggests that the quaternary ammonium ion is bound not to a negatively charged "anionic" site, but rather to some of the 14 aromatic residues that line the gorge.
Biological context
AChE (E.C. 3.1.1.7) rapidly hydrolyzes acetylcholine released into the synapse. Its catalytic activity can be represented as acetylcholine + H2O = choline + acetate. AChE is found in the synapses and at neuromuscular junctions, and on erythrocyte membranes.
Additional information
1EA5 hydrolyzes choline released into the synapse. Catalytic activity: acetylcholine + H2O = choline + acetate. Inhibitors of the enzyme AChE slow and sometimes reverse the cognitive decline experienced by individuals with Alzheimer's disease. T californica AChE is a G2 dimer in solution (see Sussman 1988). The asymmetric unit contains a monomer, with the crystallographic 2-fold axis relating the two monomers in a dimer. This is the highest resolution AChE determined so far. There is recent evidence (see Bucht 1996) that the gpi anchor is attached to either ser 543 or ser 544, not to sys 537.
Related diseases
Blood group, Yt system, Endplate acetylcholinesterase deficiency
About this Structure
1EA5 is a 1 chain structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.
References
- Bucht G, Hjalmarsson K. Residues in Torpedo californica acetylcholinesterase necessary for processing to a glycosyl phosphatidylinositol-anchored form. Biochim Biophys Acta. 1996 Feb 8;1292(2):223-32. PMID:8597567
- Axelsen PH, Harel M, Silman I, Sussman JL. Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-ray crystallography. Protein Sci. 1994 Feb;3(2):188-97. PMID:8003956
- Schumacher M, Camp S, Maulet Y, Newton M, MacPhee-Quigley K, Taylor SS, Friedmann T, Taylor P. Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence. Nature. 1986 Jan 30-Feb 5;319(6052):407-9. PMID:3753747 doi:10.1038/319407a0
