1k4y: Difference between revisions

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

OverviewOverview

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 StructureAbout this Structure

1K4Y is a Single protein structure of sequence from Oryctolagus cuniculus with as ligand. Active as Carboxylesterase, with EC number 3.1.1.1 Full crystallographic information is available from OCA.

ReferenceReference

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 Thu Feb 21 13:30:15 2008

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OCA

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-[[Image:1k4y.gif|left|200px]]<br /><applet load="1k4y" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1k4y.gif|left|200px]]<br /><applet load="1k4y" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1k4y, resolution 2.50&Aring;" />
 '''Crystal Structure of Rabbit Liver Carboxylesterase in Complex with 4-piperidino-piperidine'''<br />
 ==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.
+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==
-K4Y is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with 4PN as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Carboxylesterase Carboxylesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.1 3.1.1.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1K4Y OCA].
+K4Y is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with <scene name='pdbligand=4PN:'>4PN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Carboxylesterase Carboxylesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.1 3.1.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K4Y OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Bencharit, S.]]
-[[Category: Danks, M.K.]]
+[[Category: Danks, M K.]]
-[[Category: Howard-Williams, E.L.]]
+[[Category: Howard-Williams, E L.]]
-[[Category: Morton, C.L.]]
+[[Category: Morton, C L.]]
-[[Category: Potter, P.M.]]
+[[Category: Potter, P M.]]
-[[Category: Redinbo, M.R.]]
+[[Category: Redinbo, M R.]]
 [[Category: 4PN]]
 [[Category: camptothecin]]
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 [[Category: side door]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 18:52:00 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:30:15 2008''