2yay: Difference between revisions
No edit summary |
No edit summary |
||
| (8 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
< | ==The Crystal Structure of Leishmania major dUTPase in complex with substrate analogue dUpNpp== | ||
<StructureSection load='2yay' size='340' side='right'caption='[[2yay]], [[Resolution|resolution]] 1.86Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2yay]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_major Leishmania major]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YAY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YAY 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]] 1.86Å</td></tr> | |||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DUP:2-DEOXYURIDINE+5-ALPHA,BETA-IMIDO-TRIPHOSPHATE'>DUP</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=2yay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yay OCA], [https://pdbe.org/2yay PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yay RCSB], [https://www.ebi.ac.uk/pdbsum/2yay PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yay ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/O15826_LEIMA O15826_LEIMA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Members of the Leishmania genus are the causative agents of the life-threatening disease leishmaniasis. New drugs are being sought due to increasing resistance and adverse side effects with current treatments. The knowledge that dUTPase is an essential enzyme and that the all alpha-helical dimeric kinetoplastid dUTPases have completely different structures compared with the trimeric beta-sheet type dUTPase possessed by most organisms, including humans, make the dimeric enzymes attractive drug targets. Here, we present crystal structures of the Leishmania major dUTPase in complex with substrate analogues, the product dUMP and a substrate fragment, and of the homologous Campylobacter jejuni dUTPase in complex with a triphosphate substrate analogue. The metal-binding properties of both enzymes are shown to be dependent upon the ligand identity, a previously unseen characteristic of this family. Furthermore, structures of the Leishmania enzyme in the presence of dUMP and deoxyuridine coupled with tryptophan fluorescence quenching indicate that occupation of the phosphate binding region is essential for induction of the closed conformation and hence for substrate binding. These findings will aid in the development of dUTPase inhibitors as potential new lead anti-trypanosomal compounds. | |||
The Crystal Structure of the Leishmania major Deoxyuridine Triphosphate Nucleotidohydrolase in Complex with Nucleotide Analogues, dUMP, and Deoxyuridine.,Hemsworth GR, Moroz OV, Fogg MJ, Scott B, Bosch-Navarrete C, Gonzalez-Pacanowska D, Wilson KS J Biol Chem. 2011 May 6;286(18):16470-81. Epub 2011 Mar 15. PMID:21454646<ref>PMID:21454646</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2yay" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DUTPase 3D structures|DUTPase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[ | |||
== | |||
< | |||
[[Category: Leishmania major]] | [[Category: Leishmania major]] | ||
[[Category: Bosch-Navarrete C]] | |||
[[Category: Bosch-Navarrete | [[Category: Fogg MJ]] | ||
[[Category: Fogg | [[Category: Gonzalez-Pacanowska D]] | ||
[[Category: Gonzalez-Pacanowska | [[Category: Hemsworth GR]] | ||
[[Category: Hemsworth | [[Category: Moroz OV]] | ||
[[Category: Moroz | [[Category: Scott B]] | ||
[[Category: Scott | [[Category: Wilson KS]] | ||
[[Category: Wilson | |||
Latest revision as of 13:48, 20 December 2023
The Crystal Structure of Leishmania major dUTPase in complex with substrate analogue dUpNppThe Crystal Structure of Leishmania major dUTPase in complex with substrate analogue dUpNpp
Structural highlights
FunctionPublication Abstract from PubMedMembers of the Leishmania genus are the causative agents of the life-threatening disease leishmaniasis. New drugs are being sought due to increasing resistance and adverse side effects with current treatments. The knowledge that dUTPase is an essential enzyme and that the all alpha-helical dimeric kinetoplastid dUTPases have completely different structures compared with the trimeric beta-sheet type dUTPase possessed by most organisms, including humans, make the dimeric enzymes attractive drug targets. Here, we present crystal structures of the Leishmania major dUTPase in complex with substrate analogues, the product dUMP and a substrate fragment, and of the homologous Campylobacter jejuni dUTPase in complex with a triphosphate substrate analogue. The metal-binding properties of both enzymes are shown to be dependent upon the ligand identity, a previously unseen characteristic of this family. Furthermore, structures of the Leishmania enzyme in the presence of dUMP and deoxyuridine coupled with tryptophan fluorescence quenching indicate that occupation of the phosphate binding region is essential for induction of the closed conformation and hence for substrate binding. These findings will aid in the development of dUTPase inhibitors as potential new lead anti-trypanosomal compounds. The Crystal Structure of the Leishmania major Deoxyuridine Triphosphate Nucleotidohydrolase in Complex with Nucleotide Analogues, dUMP, and Deoxyuridine.,Hemsworth GR, Moroz OV, Fogg MJ, Scott B, Bosch-Navarrete C, Gonzalez-Pacanowska D, Wilson KS J Biol Chem. 2011 May 6;286(18):16470-81. Epub 2011 Mar 15. PMID:21454646[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||