7s3f: Difference between revisions
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==Structure of cofactor pyridoxal 5-phosphate bound human ornithine decarboxylase in complex with its inhibitor 1-amino-oxy-3-aminopropane== | |||
<StructureSection load='7s3f' size='340' side='right'caption='[[7s3f]], [[Resolution|resolution]] 2.49Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7s3f]] 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=7S3F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S3F FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.49Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=XAP:3-AMINOOXY-1-AMINOPROPANE'>XAP</scene></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=7s3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s3f OCA], [https://pdbe.org/7s3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s3f RCSB], [https://www.ebi.ac.uk/pdbsum/7s3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s3f ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DCOR_HUMAN DCOR_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC-APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 A resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA's high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate-binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors. | |||
Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.,Zhou XE, Suino-Powell K, Schultz CR, Aleiwi B, Brunzelle JS, Lamp J, Vega IE, Ellsworth E, Bachmann AS, Melcher K Biochem J. 2021 Dec 10;478(23):4137-4149. doi: 10.1042/BCJ20210647. PMID:34796899<ref>PMID:34796899</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7s3f" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Ornithine decarboxylase|Ornithine decarboxylase]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Vega | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Aleiwi B]] | |||
[[Category: Bachmann AS]] | |||
[[Category: Brunzelle JS]] | |||
[[Category: Ellsworth E]] | |||
[[Category: Lamp J]] | |||
[[Category: Melcher K]] | |||
[[Category: Schultz CR]] | |||
[[Category: Suino-Powell K]] | |||
[[Category: Vega IE]] | |||
[[Category: Zhou XE]] | |||
Latest revision as of 19:42, 18 October 2023
Structure of cofactor pyridoxal 5-phosphate bound human ornithine decarboxylase in complex with its inhibitor 1-amino-oxy-3-aminopropaneStructure of cofactor pyridoxal 5-phosphate bound human ornithine decarboxylase in complex with its inhibitor 1-amino-oxy-3-aminopropane
Structural highlights
FunctionPublication Abstract from PubMedOrnithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC-APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 A resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA's high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate-binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors. Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.,Zhou XE, Suino-Powell K, Schultz CR, Aleiwi B, Brunzelle JS, Lamp J, Vega IE, Ellsworth E, Bachmann AS, Melcher K Biochem J. 2021 Dec 10;478(23):4137-4149. doi: 10.1042/BCJ20210647. PMID:34796899[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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