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ORTHORHOMBIC FORM OF TORPEDO CALIFORNICA ACETYLCHOLINESTERASE (ACHE) COMPLEXED WITH BIS-ACTING GALANTHAMINE DERIVATIVE

(see also 1W4L, 1W6R, and AChE bivalent inhibitors (Part II))

Biological Context

Alzheimer's disease is a disorder that attacks the central nervous system through progressive degeneration of its neurons. Patients with this disease develop dementia which becomes more severe as the disease progresses. It was suggested that symptoms of Alzheimer's disease are caused by a decrease in the activity of cholinergic neocortical and hippocampal neurons. Treatment for Alzheimer's disease by acetylcholine (ACh) precursors and cholinergic agonists was ineffective or caused side effects. The enzyme acetylcholinesterase (AChE) hydrolyses ACh, resulting in termination of cholinergic neurotransmission. Therefore, compounds which inhibit AChE might significantly increase the levels of ACh depleted by Alzheimer's disease. Galanthamine (1; GAL; Reminyl) is an AChE inhibitor and it is currently used for paliative therapy of Alzheimer's disease. The X-ray structure of Torpedo californica AChE (TcAChE) in complex with a bivalent galanthamine iminium derivative (4) was determined at 2.30 Å.

1w76, resolution 2.30Å ()
Sites:	, , , , and
Ligands:	,
Activity:	Acetylcholinesterase, with EC number 3.1.1.7
Related:	1acj, 1acl, 1amn, 1ax9, 1cfj, 1dx6, 1e3q, 1e66, 1ea5, 1eea, 1eve, 1fss, 1gpk, 1gpn, 1gqr, 1gqs, 1h22, 1h23, 1hbj, 1jga, 1jgb, 1jjb, 1oce, 1odc, 1qid, 1qie, 1qif, 1qig, 1qih, 1qii, 1qij, 1qik, 1qim, 1qti, 1som, 1ut6, 1vot, 1vxo, 1vxr, 1w4l, 1w6r, 1w75, 2ace, 2ack, 2dfp, 3ace, 4ace
Structural annotation: Resources: CATH : 1W76A00, 1W76B00 InterPro : Ipr000997, Ipr002018, Ipr000908 Pfam : PF00135 UniProt : P04058
Functional annotation: Cellular component: synapse membrane cell junction Biological process: acetylcholine catabolic process in synaptic cleft neurotransmitter catabolic process Molecular function: cholinesterase activity GPI anchor binding acetylcholinesterase activity hydrolase activity
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, PDBsum, RCSB
Coordinates:	save as pdb, mmCIF, xml

About this Structure

1W76 is a 2 chains structure of sequences from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources

For additional information, see: Alzheimer's Disease

Reference

• Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:15563167 doi:10.1021/ja0466154

Page seeded by OCA on Wed Feb 18 09:11:22 2009