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1u65
From Proteopedia
| 1u65, resolution 2.61Å () | |||||||||
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| Ligands: | , , | ||||||||
| Non-Standard Residues: | , , , | ||||||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||||||
| Domains: | Esterase_lipase, COesterase | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB, TOPSAN | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
The Crystal Structure of the Complex of the Anticancer Prodrug CPT-11 with Torpedo californica Acetylcholinesterase
(see also AChE bivalent inhibitors (Part II))
The anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino-]carbonyloxycamptothecin (CPT-11) is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. It is hydrolyzed by carboxylesterases to yield 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I poison. However, upon high-dose intravenous administration of CPT-11, a cholinergic syndrome is observed that can be ameliorated by atropine. Previous studies have indicated that CPT-11 can inhibit acetylcholinesterase (AChE), and here, we provide a detailed analysis of the inhibition of AChE by CPT-11 and by structural analogs. These studies demonstrate that the terminal dipiperidino moiety in CPT-11 plays a major role in enzyme inhibition, and this has been confirmed by X-ray crystallographic studies of a complex of the drug with Torpedo californica AChE. Our results indicate that CPT-11 binds within the active site gorge of the protein in a fashion similar to that observed with the Alzheimer drug donepezil. The 3D structure of the CPT-11/AChE complex also permits modeling of CPT-11 complexed with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug to the active metabolite. Overall, the results presented here clarify the mechanism of AChE inhibition by CPT-11 and detail the interaction of the drug with the protein. These studies may allow the design of both novel camptothecin analogs that would not inhibit AChE and new AChE inhibitors derived from the camptothecin scaffold.
The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action., Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM, Mol Pharmacol. 2005 Jun;67(6):1874-81. Epub 2005 Mar 16. PMID:15772291
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
(yellow) interacts with 13 residues of the the of TcAChE from residue Trp84 at the bottom to Phe284 at its top. Nine of these residues are (Tyr70, Trp84, Tyr121, Trp279, Phe284, Phe330, Phe331, Tyr334, and His440; colored darkmagenta). The contacts made by the drug at the bottom of the gorge involve with Trp84, Tyr121, Phe331, and His440 and, especially, a stacking interaction with Phe330. The carbamate moiety of CPT-11 is located near residues . Carbon C9 (shown in magenta) of the carbamate linkage in CPT-11, is 9.3 Å from Oγ, the nucleophilic atom of the three catalytic residues Ser200, His440, and Glu327. The steric clashes between CPT-11 and TcAChE residues prevents the positioning CPT-11 near the Ser200 Oγ (where hydrolysis could occur), therefore, TcAChE can not hydrolyze CPT-11.
About this Structure
1U65 is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.
Reference
The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action., Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM, Mol Pharmacol. 2005 Jun;67(6):1874-81. Epub 2005 Mar 16. PMID:15772291
Page seeded by OCA on Tue Jul 29 11:45:13 2008
Proteopedia Page Contributors and Editors (what is this?)
Alexander Berchansky, OCA, Michal Harel, Joel L. Sussman, Jaime Prilusky
Categories: Acetylcholinesterase | Single protein | Torpedo californica | Brumshtein, B. | Harel, M. | Hyatt, J L. | ISPC, Israel Structural Proteomics Center. | Morton, C L. | Potter, P M. | Silman, I. | Sussman, J L. | Wadkins, R W. | Anticancer prodrug cpt-11 | ISPC | Israel Structural Proteomics Center | Structural genomic | Torpedo ache
