5ek4: Difference between revisions

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'''Unreleased structure'''
==Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with NLG919 analogue==
<StructureSection load='5ek4' size='340' side='right' caption='[[5ek4]], [[Resolution|resolution]] 2.64&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ek4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EK4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EK4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5PF:(1~{R})-1-CYCLOHEXYL-2-[(5~{S})-6-FLUORANYL-5~{H}-IMIDAZO[1,5-B]ISOINDOL-5-YL]ETHANOL'>5PF</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ek3|5ek3]], [[5ek2|5ek2]]</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=5ek4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ek4 OCA], [http://pdbe.org/5ek4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ek4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ek4 PDBsum]</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 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.


The entry 5ek4 is ON HOLD  until Paper Publication
Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1.,Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, Liao FY, Fan YS, Wu MH, Hsiao WC, Hsueh CC, Lin SY, Cheng CY, Tu CH, Lee LC, Cheng MF, Shia KS, Shih C, Wu SY J Med Chem. 2015 Dec 21. PMID:26642377<ref>PMID:26642377</ref>


Authors: Wu, S.Y., Peng, Y.H., Wu, J.S.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
Description: Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with NLG919 analogue
<div class="pdbe-citations 5ek4" style="background-color:#fffaf0;"></div>
[[Category: Unreleased Structures]]
== References ==
[[Category: Wu, S.Y]]
<references/>
[[Category: Wu, J.S]]
__TOC__
[[Category: Peng, Y.H]]
</StructureSection>
[[Category: Indoleamine 2,3-dioxygenase]]
[[Category: Peng, Y H]]
[[Category: Wu, J S]]
[[Category: Wu, S Y]]
[[Category: Ido1]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

Revision as of 15:40, 23 December 2015

Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with NLG919 analogueCrystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with NLG919 analogue

Structural highlights

5ek4 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Activity:Indoleamine 2,3-dioxygenase, with EC number 1.13.11.52
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

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 PubMed

Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.

Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1.,Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, Liao FY, Fan YS, Wu MH, Hsiao WC, Hsueh CC, Lin SY, Cheng CY, Tu CH, Lee LC, Cheng MF, Shia KS, Shih C, Wu SY J Med Chem. 2015 Dec 21. PMID:26642377[2]

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

References

  1. ↑ Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007 Aug 1;67(15):7082-7. PMID:17671174 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1872
  2. ↑ Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, Liao FY, Fan YS, Wu MH, Hsiao WC, Hsueh CC, Lin SY, Cheng CY, Tu CH, Lee LC, Cheng MF, Shia KS, Shih C, Wu SY. Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1. J Med Chem. 2015 Dec 21. PMID:26642377 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01390

5ek4, resolution 2.64Å

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