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==Crystal structure of IDO1 in complex with Apoxidole-1== | ==Crystal structure of IDO1 in complex with Apoxidole-1== | ||
<StructureSection load='8abx' size='340' side='right'caption='[[8abx]]' scene=''> | <StructureSection load='8abx' size='340' side='right'caption='[[8abx]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ABX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ABX FirstGlance]. <br> | <table><tr><td colspan='2'>[[8abx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ABX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ABX FirstGlance]. <br> | ||
</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=8abx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8abx OCA], [https://pdbe.org/8abx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8abx RCSB], [https://www.ebi.ac.uk/pdbsum/8abx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8abx ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N2U:O2-tert-butyl+O3-ethyl+O6-methyl+(2S,6R)-6-(1-methylindol-2-yl)-2,5-dihydro-1H-pyridine-2,3,6-tricarboxylate'>N2U</scene>, <scene name='pdbligand=N39:O1-tert-butyl+O2-ethyl+O5-methyl+(E,5R)-5-(1-methylindol-2-yl)-5-[(4-methylphenyl)sulfonylamino]pent-2-ene-1,2,5-tricarboxylate'>N39</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase Indoleamine 2,3-dioxygenase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=8abx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8abx OCA], [https://pdbe.org/8abx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8abx RCSB], [https://www.ebi.ac.uk/pdbsum/8abx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8abx ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://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 == | |||
Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research. | |||
Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.,Davies C, Dotsch L, Ciulla MG, Hennes E, Yoshida K, Gasper R, Scheel R, Sievers S, Strohmann C, Kumar K, Ziegler S, Waldmann H Angew Chem Int Ed Engl. 2022 Aug 12:e202209374. doi: 10.1002/anie.202209374. PMID:35959923<ref>PMID:35959923</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8abx" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Indoleamine 2,3-dioxygenase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Dotsch L]] | [[Category: Dotsch, L]] | ||
[[Category: Gasper R]] | [[Category: Gasper, R]] | ||
[[Category: Waldmann H]] | [[Category: Waldmann, H]] | ||
[[Category: Ziegler S]] | [[Category: Ziegler, S]] | ||
[[Category: 3-dioxygenase 1]] | |||
[[Category: Heme-binding protein]] | |||
[[Category: Indoleamine 2]] | |||
[[Category: Natural product]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 09:46, 31 August 2022
Crystal structure of IDO1 in complex with Apoxidole-1Crystal structure of IDO1 in complex with Apoxidole-1
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 PubMedNatural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research. Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.,Davies C, Dotsch L, Ciulla MG, Hennes E, Yoshida K, Gasper R, Scheel R, Sievers S, Strohmann C, Kumar K, Ziegler S, Waldmann H Angew Chem Int Ed Engl. 2022 Aug 12:e202209374. doi: 10.1002/anie.202209374. PMID:35959923[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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