View source for 9hdt


==Variant T321N of Orotidine 5'-monophosphate decarboxylase-domain of human UMPS in complex with Deoxyuridine-5'-monophosphate (Deoxy UMP) at 1.3 Angstroms resolution==
<StructureSection load='9hdt' size='340' side='right'caption='[[9hdt]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9hdt]] is a 1 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=9HDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HDT 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]] 1.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSS:S-MERCAPTOCYSTEINE'>CSS</scene>, <scene name='pdbligand=DU:2-DEOXYURIDINE-5-MONOPHOSPHATE'>DU</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</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=9hdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hdt OCA], [https://pdbe.org/9hdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hdt RCSB], [https://www.ebi.ac.uk/pdbsum/9hdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hdt ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:[https://omim.org/entry/258900 258900]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies.<ref>PMID:9042911</ref> 
== Function ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
With an extraordinary rate enhancement of 10(17) compared to the uncatalyzed reaction and no need for a cofactor, orotidine 5'-monophosphate decarboxylase (OMPDC) is considered one of the most efficient enzymes. Its mechanism has fascinated researchers for over 50 years. In this study, we used high-resolution X-ray crystallography to examine the molecular interactions between the active site of human OMPDC and various natural and synthetic ligands, including transition-state and product analogues, at the atomic level. Additionally, we evaluated their binding affinities with isothermal titration calorimetry (ITC). During protein expression and subsequent structure analysis, we identified nucleotides xanthosine-5'-monophosphate (XMP) and thymidine-5'-monophosphate (dTMP) bound to the active sites of OMPDC and its Thr321Asn variant, respectively, and confirmed their high binding affinities through ITC. Chemically, we investigated the role of the ribose 2'-OH group using 2'-deoxy OMP and 2'-SH UMP, focusing on validating key binding interactions within the nucleoside moiety. To further explore these interactions, we modified the heterocycles (e.g., GMP and CMP) and synthesized a new transition-state analogue, cyanuryl-5'-monophosphate (YMP). YMP exhibited strong affinity for OMPDC and formed an additional hydrogen bond with a nearby water molecule. However, this enthalpically favorable interaction resulted in an entropic penalty compared to the best-known OMPDC inhibitor, BMP, leading to similar affinities. To address this, we synthesized 5-methyl OMP to further improve ligand-enzyme interactions. This modification enhanced stabilization within the hydrophobic pocket through van der Waals forces, paving the way for designing more effective OMPDC inhibitors with specific substitutions aimed at optimizing binding affinity and enzyme inhibition.

Expected and Unexpected "Guests" at the Active Site of Human Orotidine 5'-Monophosphate Decarboxylase.,Kirck LL, Santagostino E, Brandhoff L, Simeth NA, Tittmann K Biochemistry. 2025 Oct 8. doi: 10.1021/acs.biochem.5c00459. PMID:41058608<ref>PMID:41058608</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9hdt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kirck LL]]
[[Category: Santagostino E]]
[[Category: Tittmann K]]