This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

1u65

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Current revision

Ache W. CPT-11

Structural highlights

1u65 is a 1 chain structure with sequence from Tetronarce californica. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.61Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT, TOPSAN

Function

ACES_TETCF Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM. 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. Mol Pharmacol. 2005 Jun;67(6):1874-81. Epub 2005 Mar 16. PMID:15772291 doi:http://dx.doi.org/10.1124/mol.104.009944

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1u65"

@@ Line 3: / Line 3: @@
 <StructureSection load='1u65' size='340' side='right'caption='[[1u65]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1u65]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Torpedo_californica Torpedo californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U65 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1U65 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1u65]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Tetronarce_californica Tetronarce californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U65 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1U65 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CP0:(4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3,4 6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL+1,4-BIPIPERIDINE-1-CARBOXYLATE'>CP0</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.61&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CP0:(4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3,4 6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL+1,4-BIPIPERIDINE-1-CARBOXYLATE'>CP0</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1u65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u65 OCA], [http://pdbe.org/1u65 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1u65 RCSB], [http://www.ebi.ac.uk/pdbsum/1u65 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1u65 ProSAT], [http://www.topsan.org/Proteins/ISPC/1u65 TOPSAN]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1u65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u65 OCA], [https://pdbe.org/1u65 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1u65 RCSB], [https://www.ebi.ac.uk/pdbsum/1u65 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1u65 ProSAT], [https://www.topsan.org/Proteins/ISPC/1u65 TOPSAN]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ACES_TORCA ACES_TORCA]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions.
+[https://www.uniprot.org/uniprot/ACES_TETCF ACES_TETCF] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 31: / Line 31: @@
 ==See Also==
-*[[AChE inhibitors and substrates|AChE inhibitors and substrates]]
 *[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]]
-*[[User:Boris Brumshtein|User:Boris Brumshtein]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Acetylcholinesterase]]
 [[Category: Large Structures]]
-[[Category: Torpedo californica]]
+[[Category: Tetronarce californica]]
-[[Category: Brumshtein, B]]
+[[Category: Brumshtein B]]
-[[Category: Harel, M]]
+[[Category: Harel M]]
-[[Category: Hyatt, J L]]
+[[Category: Hyatt JL]]
-[[Category: ISPC, Israel Structural Proteomics Center]]
+[[Category: Morton CL]]
-[[Category: Morton, C L]]
+[[Category: Potter PM]]
-[[Category: Potter, P M]]
+[[Category: Silman I]]
-[[Category: Silman, I]]
+[[Category: Sussman JL]]
-[[Category: Sussman, J L]]
+[[Category: Wadkins RW]]
-[[Category: Wadkins, R W]]
-[[Category: Anticancer prodrug cpt-11]]
-[[Category: Hydrolase]]
-[[Category: Structural genomic]]
-[[Category: Torpedo ache]]

1u65

From Proteopedia

Current revision

Ache W. CPT-11

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox