1K4Y

Crystal Structure of Rabbit Liver Carboxylesterase in Complex with 4-piperidino-piperidine

Summary for 1K4Y

• Entry DOI: 10.2210/pdb1k4y/pdb
• Descriptor: LIVER CARBOXYLESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: hydrolase, esterase, side door, camptothecin, irinotecan
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 1
• Total formula weight: 60529.10

Authors

Bencharit, S.,Morton, C.L.,Howard-Williams, E.L.,Danks, M.K.,Potter, P.M.,Redinbo, M.R. (deposition date: 2001-10-09, release date: 2002-05-01, Last modification date: 2024-10-09)

Primary citation

Bencharit, S.,Morton, C.L.,Howard-Williams, E.L.,Danks, M.K.,Potter, P.M.,Redinbo, M.R.
Structural insights into CPT-11 activation by mammalian carboxylesterases.
Nat.Struct.Biol., 9:337-342, 2002

PubMed 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.

PubMed: 11967565
DOI: 10.1038/nsb790

Experimental method

X-RAY DIFFRACTION (2.5 Å)