1K4Y: Crystal Structure Of Rabbit Liver Carboxylesterase In Complex With 4- Piperidino-Piperidine

Citation:
Abstract
Mammalian carboxylesterases cleave the anticancer prodrug CPT-11 (Irinotecan) into SN-38, a potent topoisomerase I poison, and 4-piperidino-piperidine (4PP). We present the 2.5 A crystal structure of rabbit liver carboxylesterase (rCE), the most efficient enzyme known to activate CPT-11 in this manner, in complex with the leaving group 4PP. 4PP is observed bound adjacent to a high-mannose Asn-linked glycosylation site on the surface of rCE. This product-binding site is separated from the catalytic gorge by a thin wall of amino acid side chains, suggesting that 4PP may be released through this secondary product exit pore. The crystallographic observation of a leaving group bound on the surface of rCE supports the 'back door' product exit site proposed for the acetylcholinesterases. These results may facilitate the design of improved anticancer drugs or enzymes for use in viral-directed cancer cotherapies.
PDB ID: 1K4YDownload
MMDB ID: 19258
PDB Deposition Date: 2001/10/9
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 1K4Y: monomeric; determined by author
Molecular Components in 1K4Y
Label Count Molecule
Protein (1 molecule)
1
Liver Carboxylesterase(Gene symbol: LOC100009551)
Molecule annotation
Chemicals (8 molecules)
1
4
2
3
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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