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6pyy

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Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PF-06840003 in Active Site and Exo site

Structural highlights

6pyy is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

T23O_HUMAN Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity).

Publication Abstract from PubMed

Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxygenases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400-fold higher inhibition activity toward hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offers a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is approximately 40 A away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO.

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase.,Pham KN, Lewis-Ballester A, Yeh SR J Am Chem Soc. 2019 Nov 27;141(47):18771-18779. doi: 10.1021/jacs.9b08871. Epub, 2019 Nov 14. PMID:31682426^[1]

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

References

↑ Pham KN, Lewis-Ballester A, Yeh SR. Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase. J Am Chem Soc. 2019 Nov 27;141(47):18771-18779. doi: 10.1021/jacs.9b08871. Epub, 2019 Nov 14. PMID:31682426 doi:http://dx.doi.org/10.1021/jacs.9b08871

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6pyy"

Categories: Homo sapiens | Large Structures | Lewis-Ballester A | Pham KN | Yeh SR

@@ Line 3: / Line 3: @@
 <StructureSection load='6pyy' size='340' side='right'caption='[[6pyy]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pyy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PYY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PYY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pyy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PYY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PYY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H7S:(3S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione'>H7S</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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]] 2.4&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Tryptophan_2,3-dioxygenase Tryptophan 2,3-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.13.11.11 1.13.11.11] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H7S:(3S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione'>H7S</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=6pyy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pyy OCA], [http://pdbe.org/6pyy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pyy RCSB], [http://www.ebi.ac.uk/pdbsum/6pyy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pyy ProSAT]</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=6pyy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pyy OCA], [https://pdbe.org/6pyy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pyy RCSB], [https://www.ebi.ac.uk/pdbsum/6pyy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pyy ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/T23O_HUMAN T23O_HUMAN]] Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity).
+[https://www.uniprot.org/uniprot/T23O_HUMAN T23O_HUMAN] Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity).
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6pyy" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Dioxygenase 3D structures|Dioxygenase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Tryptophan 2,3-dioxygenase]]
+[[Category: Lewis-Ballester A]]
-[[Category: Lewis-Ballester, A]]
+[[Category: Pham KN]]
-[[Category: Pham, K N]]
+[[Category: Yeh SR]]
-[[Category: Yeh, S R]]
-[[Category: Oxidoreductase]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
-[[Category: Pf-06840003]]
-[[Category: Tryptophan dioxygenase]]

6pyy

From Proteopedia

Current revision

Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PF-06840003 in Active Site and Exo site

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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