2bag: Difference between revisions

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[[Image:2bag.gif|left|200px]]
{{Seed}}
[[Image:2bag.png|left|200px]]


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{{STRUCTURE_2bag|  PDB=2bag  |  SCENE=  }}  
{{STRUCTURE_2bag|  PDB=2bag  |  SCENE=  }}  


'''3D Structure of Torpedo californica acetylcholinesterase complexed with Ganstigmine'''
===3D Structure of Torpedo californica acetylcholinesterase complexed with Ganstigmine===




==Overview==
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Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.
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{{ABSTRACT_PUBMED_16913695}}


==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819)., Bartolucci C, Siotto M, Ghidini E, Amari G, Bolzoni PT, Racchi M, Villetti G, Delcanale M, Lamba D, J Med Chem. 2006 Aug 24;49(17):5051-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16913695 16913695]
Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819)., Bartolucci C, Siotto M, Ghidini E, Amari G, Bolzoni PT, Racchi M, Villetti G, Delcanale M, Lamba D, J Med Chem. 2006 Aug 24;49(17):5051-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16913695 16913695]
"Back door" opening implied by the crystal structure of a carbamoylated acetylcholinesterase., Bartolucci C, Perola E, Cellai L, Brufani M, Lamba D, Biochemistry. 1999 May 4;38(18):5714-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10231521 10231521]
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine., Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I, Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11888271 11888271]
Long chain analogs of physostigmine as potential drugs for Alzheimer's disease: new insights into the mechanism of action in the inhibition of acetylcholinesterase., Perola E, Cellai L, Lamba D, Filocamo L, Brufani M, Biochim Biophys Acta. 1997 Nov 14;1343(1):41-50. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9428657 9428657]
[[Category: Acetylcholinesterase]]
[[Category: Acetylcholinesterase]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: Neurotransmitter cleavage]]
[[Category: Neurotransmitter cleavage]]
[[Category: Serine hydrolase]]
[[Category: Serine hydrolase]]
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