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==Crystal structure of the Pseudomonas aeruginosa dihydropyrimidinase complexed with 5-AU== | ==Crystal structure of the Pseudomonas aeruginosa dihydropyrimidinase complexed with 5-AU== | ||
<StructureSection load='7e3u' size='340' side='right'caption='[[7e3u]]' scene=''> | <StructureSection load='7e3u' size='340' side='right'caption='[[7e3u]], [[Resolution|resolution]] 2.16Å' 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=7E3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E3U FirstGlance]. <br> | <table><tr><td colspan='2'>[[7e3u]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E3U 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=7e3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e3u OCA], [https://pdbe.org/7e3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e3u RCSB], [https://www.ebi.ac.uk/pdbsum/7e3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e3u 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=WBU:5-AMINO-1H-PYRIMIDINE-2,4-DIONE'>WBU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydropyrimidinase Dihydropyrimidinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.2 3.5.2.2] </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=7e3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e3u OCA], [https://pdbe.org/7e3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e3u RCSB], [https://www.ebi.ac.uk/pdbsum/7e3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e3u ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/HYDA_PSEAE HYDA_PSEAE]] Catalyzes the hydrolysis of dihydropyrimidines and of the structurally related DL-5-mono-substituted hydantoins, to produce N-carbamoyl-D-amino acids. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dihydropyrimidinase (DHPase) is a key enzyme for pyrimidine degradation. DHPase contains a binuclear metal center in which two Zn ions are bridged by a posttranslationally carbamylated lysine. DHPase catalyzes the hydrolysis of dihydrouracil to N-carbamoyl-beta-alanine. Whether 5-aminouracil (5-AU), a thymine antagonist and an anticancer drug that can block DNA synthesis and induce replication stress, can interact with DHPase remains to be investigated. In this study, we determined the crystal structure of Pseudomonas aeruginosa DHPase (PaDHPase) complexed with 5-AU at 2.1 A resolution (PDB entry 7E3U). This complexed structure revealed that 5-AU interacts with Znalpha (3.2 A), Znbeta (3.0 A), the main chains of residues Ser289 (2.8 A) and Asn337 (3.3 A), and the side chain of residue Tyr155 (2.8 A). These residues are also known as the substrate-binding sites of DHPase. Dynamic loop I (amino acid residues Pro65-Val70) in PaDHPase is not involved in the binding of 5-AU. The fluorescence quenching analysis and site-directed mutagenesis were used to confirm the binding mode revealed by the complexed crystal structure. The 5-AU binding mode of PaDHPase is, however, different from that of 5-fluorouracil, the best-known fluoropyrimidine used for anticancer therapy. These results provide molecular insights that may facilitate the development of new inhibitors targeting DHPase and constitute the 5-AU interactome. | |||
Molecular Insights into How the Dimetal Center in Dihydropyrimidinase Can Bind the Thymine Antagonist 5-Aminouracil: A Different Binding Mode from the Anticancer Drug 5-Fluorouracil.,Lin ES, Luo RH, Yang YC, Huang CY Bioinorg Chem Appl. 2022 Feb 14;2022:1817745. doi: 10.1155/2022/1817745., eCollection 2022. PMID:35198016<ref>PMID:35198016</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7e3u" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Dihydropyrimidinase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Huang | [[Category: Huang, C Y]] | ||
[[Category: Huang | [[Category: Huang, Y H]] | ||
[[Category: Lin | [[Category: Lin, E S]] | ||
[[Category: Luo | [[Category: Luo, R H]] | ||
[[Category: Yang | [[Category: Yang, Y C]] | ||
[[Category: Hydrolase]] | |||
Revision as of 10:17, 9 March 2022
Crystal structure of the Pseudomonas aeruginosa dihydropyrimidinase complexed with 5-AUCrystal structure of the Pseudomonas aeruginosa dihydropyrimidinase complexed with 5-AU
Structural highlights
Function[HYDA_PSEAE] Catalyzes the hydrolysis of dihydropyrimidines and of the structurally related DL-5-mono-substituted hydantoins, to produce N-carbamoyl-D-amino acids. Publication Abstract from PubMedDihydropyrimidinase (DHPase) is a key enzyme for pyrimidine degradation. DHPase contains a binuclear metal center in which two Zn ions are bridged by a posttranslationally carbamylated lysine. DHPase catalyzes the hydrolysis of dihydrouracil to N-carbamoyl-beta-alanine. Whether 5-aminouracil (5-AU), a thymine antagonist and an anticancer drug that can block DNA synthesis and induce replication stress, can interact with DHPase remains to be investigated. In this study, we determined the crystal structure of Pseudomonas aeruginosa DHPase (PaDHPase) complexed with 5-AU at 2.1 A resolution (PDB entry 7E3U). This complexed structure revealed that 5-AU interacts with Znalpha (3.2 A), Znbeta (3.0 A), the main chains of residues Ser289 (2.8 A) and Asn337 (3.3 A), and the side chain of residue Tyr155 (2.8 A). These residues are also known as the substrate-binding sites of DHPase. Dynamic loop I (amino acid residues Pro65-Val70) in PaDHPase is not involved in the binding of 5-AU. The fluorescence quenching analysis and site-directed mutagenesis were used to confirm the binding mode revealed by the complexed crystal structure. The 5-AU binding mode of PaDHPase is, however, different from that of 5-fluorouracil, the best-known fluoropyrimidine used for anticancer therapy. These results provide molecular insights that may facilitate the development of new inhibitors targeting DHPase and constitute the 5-AU interactome. Molecular Insights into How the Dimetal Center in Dihydropyrimidinase Can Bind the Thymine Antagonist 5-Aminouracil: A Different Binding Mode from the Anticancer Drug 5-Fluorouracil.,Lin ES, Luo RH, Yang YC, Huang CY Bioinorg Chem Appl. 2022 Feb 14;2022:1817745. doi: 10.1155/2022/1817745., eCollection 2022. PMID:35198016[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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