3ZV7

Torpedo californica Acetylcholinesterase Inhibition by Bisnorcymserine

Summary for 3ZV7

• Entry DOI: 10.2210/pdb3zv7/pdb
• 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 1U65 1UT6 1VOT 1VXO 1VXR 1W4L 1W6R 1W75 1W76 1ZGB 1ZGC 2ACE 2ACK 2C4H 2C58 2C5F 2C5G 2CEK 2CKM 2CMF 2DFP 2J3D 2J3Q 2J4F 2V96 2V97 2V98 2VA9 2VJA 2VJB 2VJC 2VJD 2VQ6 2VT6 2VT7 2W6C 2W9I 2WFZ 2WG0 2WG1 2WG2 2XI4 3ACE 4ACE
• Descriptor: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, PENTAETHYLENE GLYCOL, ... (10 entities in total)
• Functional Keywords: hydrolase, neurotransmitter cleavage, anti-alzheimer drug
• Biological source: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• Total number of polymer chains: 1
• Total formula weight: 63152.63

Authors

Bartolucci, C.,Stojan, J.,Greig, N.H.,Lamba, D. (deposition date: 2011-07-24, release date: 2012-05-23, Last modification date: 2024-10-16)

Primary citation

Bartolucci, C.,Stojan, J.,Yu, Q.S.,Greig, N.H.,Lamba, D.
Kinetics of Torpedo Californica Acetylcholinesterase Inhibition by Bisnorcymserine and Crystal Structure of the Complex with its Leaving Group.
Biochem.J., 444:269-, 2012

PubMed Abstract: Natural and synthetic carbamates act as pseudo-irreversible inhibitors of AChE (acetylcholinesterase) as well as BChE (butyrylcholinesterase), two enzymes involved in neuronal function as well as in the development and progression of AD (Alzheimer's disease). The AChE mode of action is characterized by a rapid carbamoylation of the active-site Ser(200) with release of a leaving group followed by a slow regeneration of enzyme action due to subsequent decarbamoylation. The experimental AD therapeutic bisnorcymserine, a synthetic carbamate, shows an interesting activity and selectivity for BChE, and its clinical development is currently being pursued. We undertook detailed kinetic studies on the activity of the carbamate bisnorcymserine with Tc (Torpedo californica) AChE and, on the basis of the results, crystallized the complex between TcAChE and bisnorcymserine. The X-ray crystal structure showed only the leaving group, bisnoreseroline, trapped at the bottom of the aromatic enzyme gorge. Specifically, bisnoreseroline interacts in a non-covalent way with Ser(200) and His(440), disrupting the existing interactions within the catalytic triad, and it stacks with Trp(84) at the bottom of the gorge, giving rise to an unprecedented hydrogen-bonding contact. These interactions point to a dominant reversible inhibition mechanism attributable to the leaving group, bisnoreseroline, as revealed by kinetic analysis.

PubMed: 22390827
DOI: 10.1042/BJ20111675

Experimental method

X-RAY DIFFRACTION (2.26 Å)