6f0a: Difference between revisions
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==Crystal structure of human indoleamine 2,3-dioxygenase bound to a triazole inhibitor and alanine molecule.== | |||
<StructureSection load='6f0a' size='340' side='right' caption='[[6f0a]], [[Resolution|resolution]] 2.26Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f0a]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F0A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F0A FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALA:ALANINE'>ALA</scene>, <scene name='pdbligand=C82:~{N}-(4-chlorophenyl)-1~{H}-1,2,3-triazol-5-amine'>C82</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase Indoleamine 2,3-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.13.11.52 1.13.11.52] </span></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=6f0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f0a OCA], [http://pdbe.org/6f0a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f0a RCSB], [http://www.ebi.ac.uk/pdbsum/6f0a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f0a ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/I23O1_HUMAN I23O1_HUMAN]] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.<ref>PMID:17671174</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Indoleamine-2,3 dioxygenase (IDO) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO has become an attractive target for cancer treatment. We have identified a novel series of highly cell potent IDO inhibitors based on a 4-amino-1,2,3-triazole core. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a non-competitive kinetic mechanism-of-action with respect to the tryptophan substrate. Surprisingly, they bind in the tryptophan pocket, making a direct ligand interaction with the haem iron of the porphyrin cofactor. We propose that these data can be rationalised by an ordered binding mechanism in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which we propose partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO targeted drugs. | |||
Novel 4-amino-1,2,3-triazole inhibitors of indoleamine 2,3-dioxygenase form a long-lived complex with the enzyme and display exquisite cellular potency.,Alexandre J, Swan M, Latchem M, Boyall D, Pollard J, Hughes S, Westcott J Chembiochem. 2017 Dec 14. doi: 10.1002/cbic.201700560. PMID:29240291<ref>PMID:29240291</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 6f0a" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Indoleamine 2,3-dioxygenase]] | |||
[[Category: Latchem, M]] | [[Category: Latchem, M]] | ||
[[Category: Swan, M K]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Tryptophan 2 3 dioxygenase activity electron transfer activity oxidoreductase activity heme binding indoleamine 2 3 dioxygenase activity metal ion binding dioxygenase activity]] | |||
Revision as of 11:44, 27 December 2017
Crystal structure of human indoleamine 2,3-dioxygenase bound to a triazole inhibitor and alanine molecule.Crystal structure of human indoleamine 2,3-dioxygenase bound to a triazole inhibitor and alanine molecule.
Structural highlights
Function[I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1] Publication Abstract from PubMedIndoleamine-2,3 dioxygenase (IDO) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO has become an attractive target for cancer treatment. We have identified a novel series of highly cell potent IDO inhibitors based on a 4-amino-1,2,3-triazole core. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a non-competitive kinetic mechanism-of-action with respect to the tryptophan substrate. Surprisingly, they bind in the tryptophan pocket, making a direct ligand interaction with the haem iron of the porphyrin cofactor. We propose that these data can be rationalised by an ordered binding mechanism in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which we propose partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO targeted drugs. Novel 4-amino-1,2,3-triazole inhibitors of indoleamine 2,3-dioxygenase form a long-lived complex with the enzyme and display exquisite cellular potency.,Alexandre J, Swan M, Latchem M, Boyall D, Pollard J, Hughes S, Westcott J Chembiochem. 2017 Dec 14. doi: 10.1002/cbic.201700560. PMID:29240291[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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