1k4y
From Proteopedia
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Crystal Structure of Rabbit Liver Carboxylesterase in Complex with 4-piperidino-piperidine
Overview
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.
About this Structure
1K4Y is a Single protein structure of sequence from Oryctolagus cuniculus with 4PN as ligand. Active as Carboxylesterase, with EC number 3.1.1.1 Full crystallographic information is available from OCA.
Reference
Structural insights into CPT-11 activation by mammalian carboxylesterases., Bencharit S, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR, Nat Struct Biol. 2002 May;9(5):337-42. PMID:11967565
Page seeded by OCA on Tue Nov 20 18:52:00 2007
