PDBsum entry 1ea5

Hydrolase

PDB id

1ea5

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Contents

			Protein chain

					532 a.a. *

			Ligands

					NAG ×2

			Waters ×739

* Residue conservation analysis

PDB id:

1ea5

Links

Name:

Hydrolase

Title:

Native acetylcholinesterase (E.C. 3.1.1.7) from torpedo californica at 1.8a resolution

Structure:

Acetylcholinesterase. Chain: a. Synonym: ache. Ec: 3.1.1.7

Source:

Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque

Resolution:

1.80Å

R-factor:

0.185

R-free:

0.205

Authors:

M.Harel,M.Weik,I.Silman,J.L.Sussman

Key ref:

H.Dvir et al. (2002). X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement. Biochemistry, 41, 10810-10818. PubMed id: 12196020 DOI: 10.1021/bi020151+

Date:

06-Nov-00

Release date:

08-Nov-00

PROCHECK

	Headers

	References

Protein chain

P04058 (ACES_TETCF) - Acetylcholinesterase from Tetronarce californica

Seq: Struc:

Seq: Struc:					586 a.a. 532 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.3.1.1.7 - acetylcholinesterase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

acetylcholine + H2O = choline + acetate + H⁺

acetylcholine
Bound ligand (Het Group name = NAG)
matches with 41.18% similarity

H2O

choline

acetate

H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/bi020151+	Biochemistry 41:10810-10818 (2002)
PubMed id: 12196020

X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement.
H.Dvir, H.L.Jiang, D.M.Wong, M.Harel, M.Chetrit, X.C.He, G.Y.Jin, G.L.Yu, X.C.Tang, I.Silman, D.L.Bai, J.L.Sussman.

ABSTRACT

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.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20851778

N.Kitisripanya, P.Saparpakorn, P.Wolschann, and S.Hannongbua (2011).
Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method.

Nanomedicine, 7, 60-68.

21216144

Z.F.Al-Rashid, and R.P.Hsung (2011).
(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.

Bioorg Med Chem Lett, 21, 2687-2691.

19578388

Y.F.Shi, H.Y.Zhang, W.Wang, Y.Fu, Y.Xia, X.C.Tang, D.L.Bai, and X.C.He (2009).
Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors.

Acta Pharmacol Sin, 30, 1195-1203.

17657601

H.Y.Zhang, H.Yan, and X.C.Tang (2008).
Non-cholinergic effects of huperzine A: beyond inhibition of acetylcholinesterase.

Cell Mol Neurobiol, 28, 173-183.

18367440

R.A.Hemendinger, E.J.Armstrong, R.Persinski, J.Todd, J.L.Mougeot, F.Volvovitz, and J.Rosenfeld (2008).
Huperzine A provides neuroprotection against several cell death inducers using in vitro model systems of motor neuron cell death.

Neurotox Res, 13, 49-61.

16364207

R.Wang, H.Yan, and X.C.Tang (2006).
Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine.

Acta Pharmacol Sin, 27, 1.

15739192

T.K.Manojkumar, C.Cui, and K.S.Kim (2005).
Theoretical insights into the mechanism of acetylcholinesterase-catalyzed acylation of acetylcholine.

J Comput Chem, 26, 606-611.

16113998

Y.Umezawa, and M.Nishio (2005).
CH/pi hydrogen bonds as evidenced in the substrate specificity of acetylcholine esterase.

Biopolymers, 79, 248-258.

12725862

S.Bencharit, C.L.Morton, J.L.Hyatt, P.Kuhn, M.K.Danks, P.M.Potter, and M.R.Redinbo (2003).
Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.

Chem Biol, 10, 341-349.

PDB code:

1mx1

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