FEBS Lett. 1999 Dec 17;463(3):321-6.

Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.

Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL.

Source

Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.

Abstract

(-)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.

PMID:: 10606746; [PubMed - indexed for MEDLINE]

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

GALANTAMINE - HSDB

Supplemental Content

Related citations

Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs. [Proteins. 2001]
Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs.
Bartolucci C, Perola E, Pilger C, Fels G, Lamba D. Proteins. 2001 Feb 1; 42(2):182-91.
Accurate prediction of the bound conformation of galanthamine in the active site of Torpedo californica acetylcholinesterase using molecular docking. [J Mol Graph Model. 2001]
Accurate prediction of the bound conformation of galanthamine in the active site of Torpedo californica acetylcholinesterase using molecular docking.
Pilger C, Bartolucci C, Lamba D, Tropsha A, Fels G. J Mol Graph Model. 2001; 19(3-4):288-96, 374-8.
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]
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.
Greenblatt HM, Guillou C, Guénard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. J Am Chem Soc. 2004 Dec 1; 126(47):15405-11.
Review Review of the acetylcholinesterase inhibitor galanthamine. [Expert Opin Investig Drugs. 2000]
Review Review of the acetylcholinesterase inhibitor galanthamine.
Sramek JJ, Frackiewicz EJ, Cutler NR. Expert Opin Investig Drugs. 2000 Oct; 9(10):2393-402.
Review Acetylcholinesterase: a multifaceted target for structure-based drug design of anticholinesterase agents for the treatment of Alzheimer's disease. [J Mol Neurosci. 2003]
Review Acetylcholinesterase: a multifaceted target for structure-based drug design of anticholinesterase agents for the treatment of Alzheimer's disease.
Greenblatt HM, Dvir H, Silman I, Sussman JL. J Mol Neurosci. 2003; 20(3):369-83.

See reviews... See all...

Cited by 8 PubMed Central articles

Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling. [PLoS One. 2011]
Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling.
Berg L, Andersson CD, Artursson E, Hörnberg A, Tunemalm AK, Linusson A, Ekström F. PLoS One. 2011; 6(11):e26039. Epub 2011 Nov 30.
The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies. [J Biomed Sci. 2011]
The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies.
Lu SH, Wu JW, Liu HL, Zhao JH, Liu KT, Chuang CK, Lin HY, Tsai WB, Ho Y. J Biomed Sci. 2011 Jan 21; 18:8. Epub 2011 Jan 21.
(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase. [Bioorg Med Chem Lett. 2011]
(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.
Al-Rashid ZF, Hsung RP. Bioorg Med Chem Lett. 2011 May 1; 21(9):2687-91. Epub 2010 Dec 16.

See all...

Structures reported by this article

3d Structure Of Torpedo Californica Acetylcholinesterase Complexed With N-Saccharinohexyl-Galanthamine

PDB: 3I6Z

Source: Torpedo californica

Method: X-Ray Diffraction

Resolution: 2.19 Å

See all 3 structures...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Compound
PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Substance
PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Taxonomy via GenBank
Taxonomy records associated with the current articles through taxonomic information on related molecular database records (Nucleotide, Protein, Gene, SNP, Structure).
Protein
Protein translation features of primary database (GenBank) nucleotide records reported in the current articles as well as Reference Sequences (RefSeqs) that include the articles as references.
Structure
Three-dimensional structure records in the NCBI Structure database for data reported in the current articles.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resol...
Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.
FEBS Lett. 1999 Dec 17 ;463(3):321-6.

PubMed
Parenchymal cell TNF receptors contribute to inflammatory cell recruitment and r...
Parenchymal cell TNF receptors contribute to inflammatory cell recruitment and respiratory failure in Pneumocystis carinii-induced pneumonia.
J Immunol. 2008 Jul 15 ;181(2):1409-19.

PubMed
New binary polymorphisms reshape and increase resolution of the human Y chromoso...
New binary polymorphisms reshape and increase resolution of the human Y chromosomal haplogroup tree.
Genome Res. 2008 May ;18(5):830-8. Epub 2008 Apr 2 .

PubMed
Prevalence of metabolic syndrome and related characteristics in obese adolescent...
Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome.
J Clin Endocrinol Metab. 2008 Dec ;93(12):4780-6. Epub 2008 Sep 23 .

PubMed
Anti-inflammatory, antipyretic and antinociceptive activities of Tabernaemontana...
Anti-inflammatory, antipyretic and antinociceptive activities of Tabernaemontana pandacaqui Poir.
J Ethnopharmacol. 2003 Jan ;84(1):31-5.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Display Settings:

Send to:

Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.

Source

Abstract

Publication Types, MeSH Terms, Substances

Publication Types

MeSH Terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Supplemental Content

Related citations

Cited by 8 PubMed Central articles

Structures reported by this article

Related information

Recent activity

Simple NCBI Directory

Getting Started

Resources

Popular

Featured

NCBI Information