6ftq
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human beta-ureidopropionase (beta-alanine synthase) - mutant T299C== | |
| + | <StructureSection load='6ftq' size='340' side='right'caption='[[6ftq]], [[Resolution|resolution]] 2.08Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6ftq]] 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=6FTQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FTQ 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]] 2.08Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</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=6ftq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ftq OCA], [https://pdbe.org/6ftq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ftq RCSB], [https://www.ebi.ac.uk/pdbsum/6ftq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ftq ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/BUP1_HUMAN BUP1_HUMAN] Beta-ureidopropionase deficiency. The disease is caused by variants affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/BUP1_HUMAN BUP1_HUMAN] Catalyzes a late step in pyrimidine degradation (PubMed:22525402, PubMed:24526388). Converts N-carbamoyl-beta-alanine (3-ureidopropanoate) into beta-alanine, ammonia and carbon dioxide (PubMed:10415095, PubMed:10542323, PubMed:11508704, PubMed:22525402, PubMed:24526388, PubMed:29976570). Likewise, converts N-carbamoyl-beta-aminoisobutyrate (3-ureidoisobutyrate) into beta-aminoisobutyrate, ammonia and carbon dioxide (Probable).<ref>PMID:10415095</ref> <ref>PMID:10542323</ref> <ref>PMID:11508704</ref> <ref>PMID:22525402</ref> <ref>PMID:24526388</ref> <ref>PMID:29976570</ref> <ref>PMID:22525402</ref> <ref>PMID:24526388</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | beta-Ureidopropionase (betaUP) catalyzes the third step of the reductive pyrimidine catabolic pathway responsible for breakdown of uracil-, thymine- and pyrimidine-based antimetabolites such as 5-fluorouracil. Nitrilase-like betaUPs use a tetrad of conserved residues (Cys233, Lys196, Glu119 and Glu207) for catalysis and occur in a variety of oligomeric states. Positive co-operativity toward the substrate N-carbamoyl-beta-alanine and an oligomerization-dependent mechanism of substrate activation and product inhibition have been reported for the enzymes from some species but not others. Here, the activity of recombinant human betaUP is shown to be similarly regulated by substrate and product, but in a pH-dependent manner. Existing as a homodimer at pH 9, the enzyme increasingly associates to form octamers and larger oligomers with decreasing pH. Only at physiological pH is the enzyme responsive to effector binding, with N-carbamoyl-beta-alanine causing association to more active higher molecular mass species, and beta-alanine dissociation to inactive dimers. The parallel between the pH and ligand-induced effects suggests that protonation state changes play a crucial role in the allosteric regulation mechanism. Disruption of dimer-dimer interfaces by site-directed mutagenesis generated dimeric, inactive enzyme variants. The crystal structure of the T299C variant refined to 2.08 A resolution revealed high structural conservation between human and fruit fly betaUP, and supports the hypothesis that enzyme activation by oligomer assembly involves ordering of loop regions forming the entrance to the active site at the dimer-dimer interface, effectively positioning the catalytically important Glu207 in the active site. | ||
| - | + | Crystal structure and pH-dependent allosteric regulation of human beta-ureidopropionase, an enzyme involved in anticancer drug metabolism.,Maurer D, Lohkamp B, Krumpel M, Widersten M, Dobritzsch D Biochem J. 2018 Jul 31;475(14):2395-2416. doi: 10.1042/BCJ20180222. PMID:29976570<ref>PMID:29976570</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Dobritzsch | + | <div class="pdbe-citations 6ftq" style="background-color:#fffaf0;"></div> |
| - | [[Category: Maurer | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Dobritzsch D]] | ||
| + | [[Category: Maurer D]] | ||
Current revision
Crystal structure of human beta-ureidopropionase (beta-alanine synthase) - mutant T299C
| |||||||||||
