3tgm

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<StructureSection load='3tgm' size='340' side='right'caption='[[3tgm]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
<StructureSection load='3tgm' size='340' side='right'caption='[[3tgm]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3tgm]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TGM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TGM FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3tgm]] is a 2 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=3TGM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TGM FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TG:1-(1H-IMIDAZOL-1-YL)-4,4-DIPHENYLBUTAN-2-ONE'>3TG</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3czy|3czy]], [[3hok|3hok]], [[3k4f|3k4f]], [[1n45|1n45]]</div></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TG:1-(1H-IMIDAZOL-1-YL)-4,4-DIPHENYLBUTAN-2-ONE'>3TG</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HEZ:HEXANE-1,6-DIOL'>HEZ</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HMOX1, HO, HO1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Heme_oxygenase Heme oxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.3 1.14.99.3] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tgm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tgm OCA], [https://pdbe.org/3tgm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tgm RCSB], [https://www.ebi.ac.uk/pdbsum/3tgm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tgm 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=3tgm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tgm OCA], [https://pdbe.org/3tgm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tgm RCSB], [https://www.ebi.ac.uk/pdbsum/3tgm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tgm ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[https://www.uniprot.org/uniprot/HMOX1_HUMAN HMOX1_HUMAN]] Defects in HMOX1 are the cause of heme oxygenase 1 deficiency (HMOX1D) [MIM:[https://omim.org/entry/614034 614034]]. A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly.<ref>PMID:9884342</ref>
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[https://www.uniprot.org/uniprot/HMOX1_HUMAN HMOX1_HUMAN] Defects in HMOX1 are the cause of heme oxygenase 1 deficiency (HMOX1D) [MIM:[https://omim.org/entry/614034 614034]. A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly.<ref>PMID:9884342</ref>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/HMOX1_HUMAN HMOX1_HUMAN]] Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed.
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[https://www.uniprot.org/uniprot/HMOX1_HUMAN HMOX1_HUMAN] Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be approximately 15 times more potent (IC(50) = 0.27+/-0.07 microM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC(50) = 4.0+/-1.8 microM). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This "double-clamp" binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors.
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A novel, "double-clamp" binding mode for human heme oxygenase-1 inhibition.,Rahman MN, Vlahakis JZ, Vukomanovic D, Lee W, Szarek WA, Nakatsu K, Jia Z PLoS One. 2012;7(1):e29514. Epub 2012 Jan 19. PMID:22276118<ref>PMID:22276118</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3tgm" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Heme oxygenase]]
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[[Category: Homo sapiens]]
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[[Category: Human]]
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[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Jia, Z]]
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[[Category: Jia Z]]
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[[Category: Rahman, M N]]
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[[Category: Rahman MN]]
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[[Category: Alpha helix]]
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[[Category: Heme]]
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[[Category: Microsome]]
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[[Category: Oxidoreductase]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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Current revision

X-Ray Crystal Structure of Human Heme Oxygenase-1 in Complex with 1-(1H-imidazol-1-yl)-4,4-diphenyl-2 butanone

PDB ID 3tgm

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OCA

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