2YAZ

The Crystal Structure of Leishmania major dUTPase in complex dUMP

Summary for 2YAZ

• Entry DOI: 10.2210/pdb2yaz/pdb
• Related: 2CIC 2CJE 2YAY 2YB0
• Descriptor: DUTPASE, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, leishmaniasis
• Biological source: LEISHMANIA MAJOR
• Total number of polymer chains: 4
• Total formula weight: 124129.29

Authors

Hemsworth, G.R.,Moroz, O.V.,Fogg, M.J.,Scott, B.,Bosch-Navarrete, C.,Gonzalez-Pacanowska, D.,Wilson, K.S. (deposition date: 2011-02-25, release date: 2011-03-16, Last modification date: 2023-12-20)

Primary citation

Hemsworth, G.R.,Moroz, O.V.,Fogg, M.J.,Scott, B.,Bosch-Navarrete, C.,Gonzalez-Pacanowska, D.,Wilson, K.S.
The Crystal Structure of the Leishmania Major Deoxyuridine Triphosphate Nucleotidohydrolase in Complex with Nucleotide Analogues, Dump, and Deoxyuridine.
J.Biol.Chem., 286:16470-, 2011

PubMed Abstract: 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 α-helical dimeric kinetoplastid dUTPases have completely different structures compared with the trimeric β-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.

PubMed: 21454646
DOI: 10.1074/JBC.M111.224873

Experimental method

X-RAY DIFFRACTION (2.4 Å)