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Crystal structure of dUTPase from equine infectious anaemia virus; active site metal binding in a substrate analogue complex.

Dauter Z, Persson R, Rosengren AM, Nyman PO, Wilson KS, Cedergren-Zeppezauer ES
J Mol Biol 285 655-73 (1999)
Cited: 47 times
EuropePMC logo PMID: 9878436

Abstract

The X-ray structures of dUTPase from equine infectious anaemia virus (EIAV) in unliganded and complexed forms have been determined to 1.9 and 2.0 A resolution, respectively. The structures were solved by molecular replacement using Escherichia coli dUTPase as search model. The exploitation of a relatively novel refinement approach for the initial model, combining maximum likelihood refinement with stereochemically unrestrained updating of the model, proved to be of crucial importance and should be of general relevance.EIAV dUTPase is a homotrimer where each subunit folds into a twisted antiparallel beta-barrel with the N and C-terminal portions interacting with adjacent subunits. The C-terminal 14 and 17 amino acid residues are disordered in the crystal structure of the unliganded and complexed enzyme, respectively. Interactions along the 3-fold axis include a water-containing volume (size 207 A3) which has no contact with bulk solvent. It has earlier been shown that a divalent metal ion is essential for catalysis. For the first time, a putative binding site for such a metal ion, in this case Sr2+, is established. The positions of the inhibitor (the non-hydrolysable substrate analogue dUDP) and the metal ion in the complex are consistent with the location of the active centre established for trimeric dUTPase structures, in which subunit interfaces form three surface clefts lined with evolutionary conserved residues. However, a detailed comparison of the active sites of the EIAV and E. coli enzymes reveals some structural differences. The viral enzyme undergoes a small conformational change in the uracil-binding beta-hairpin structure upon dUDP binding not observed in the other known dUTPase structures.

Reviews - 1dun mentioned but not cited (1)

  1. dUTPase: the frequently overlooked enzyme encoded by many retroviruses. Hizi A, Herzig E. Retrovirology 12 70 (2015)

Articles - 1dun mentioned but not cited (2)

  1. Design of an optimal Chebyshev-expanded discrimination function for globular proteins. Fain B, Xia Y, Levitt M. Protein Sci 11 2010-2021 (2002)
  2. Purification, crystallization and preliminary crystallographic analysis of deoxyuridine triphosphate nucleotidohydrolase from Arabidopsis thaliana. Bajaj M, Moriyama H. Acta Crystallogr Sect F Struct Biol Cryst Commun 63 409-411 (2007)


Reviews citing this publication (3)

  1. DNA base damage recognition and removal: new twists and grooves. Huffman JL, Sundheim O, Tainer JA. Mutat Res 577 55-76 (2005)
  2. Equine infectious anemia and equine infectious anemia virus in 2013: a review. Cook RF, Leroux C, Issel CJ. Vet Microbiol 167 181-204 (2013)
  3. Viral dUTPases: Modulators of Innate Immunity. Ariza ME, Cox B, Martinez B, Mena-Palomo I, Zarate GJ, Williams MV. Biomolecules 12 227 (2022)

Articles citing this publication (41)

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  17. The flexible motif V of Epstein-Barr virus deoxyuridine 5'-triphosphate pyrophosphatase is essential for catalysis. Freeman L, Buisson M, Tarbouriech N, Van der Heyden A, Labbé P, Burmeister WP. J Biol Chem 284 25280-25289 (2009)
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  28. Structural Insight into African Swine Fever Virus dUTPase Reveals a Novel Folding Pattern in the dUTPase Family. Li G, Wang C, Yang M, Cao L, Fu D, Liu X, Sun D, Chen C, Wang Y, Jia Z, Yang C, Guo Y, Rao Z. J Virol 94 e01698-19 (2020)
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  39. Catalytic Cycle of the Bifunctional Enzyme Phosphoribosyl-ATP Pyrophosphohydrolase/Phosphoribosyl-AMP Cyclohydrolase. Fisher G, Pečaver E, Read BJ, Leese SK, Laing E, Dickson AL, Czekster CM, da Silva RG. ACS Catal 13 7669-7679 (2023)
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