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1u65
From Proteopedia
| 1u65, resolution 2.61Å () | |||||
|---|---|---|---|---|---|
| Ligands: | , , | ||||
| Non-Standard Residues: | , , , | ||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||
| Domains: | Esterase_lipase, COesterase | ||||
| |||||
| 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
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.
The molecule spanned the , interacting with a series of residues from Trp84 at the bottom of the gorge to Phe284 at the top. Nine of the 13 amino acids that interacted with CPT-11 were (Tyr70, Trp84, Tyr121, Trp279, Phe284, Phe330, Phe331, Tyr334, and His440). Because the kinetic data presented above indicated that the piperidinopiperidine moiety made the major contribution toward the binding of CPT-11 to AChE, we also examined the contacts made by the drug in the lower part of the gorge. These primarily included with Trp84, Tyr121, Phe331, and His440 and, in particular, a stacking interaction with Phe330. No direct H-bonds were seen between AChE and this portion of CPT-11. As a consequence of the orientation of CPT-11 within the active-site gorge, the carbamate moiety was positioned adjacent to residues . Thus C9 (shown in magenta), the carbon of the carbamate linkage in CPT-11, was 9.3 Å from Oγ, the nucleophilic atom within the catalytic triad. Any attempt to dock CPT-11 closer to Ser200 Oγ (i.e., in a position where hydrolysis could occur) met with failure because of severe steric clashes with TcAChE. These data clearly show that TcAChE is not capable of hydrolyzing 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?)
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
