Structure of Staphylococcus aureus adenylo-succinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery

Paul K. Fyfe, Alice Dawson, Marie Theres Hutchison, Scott Cameron, William N. Hunter

Research output: Contribution to journalArticle

12 Citations (Scopus)
12 Downloads (Pure)

Abstract

The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

Original languageEnglish
Pages (from-to)881-888
Number of pages8
JournalActa Crystallographica Section D: Biological Crystallography
Volume66
Issue number8
Early online date9 Jul 2010
DOIs
Publication statusPublished - 1 Aug 2010
Externally publishedYes

Fingerprint

Lyases
Succinic Acid
Staphylococcus aureus
Catalytic Domain
Enzymes
Adenosine Monophosphate
Adenylosuccinate Lyase
Purines
Fumarates
Oxalates
Crystallization
Artifacts
Escherichia coli
Survival
Therapeutics

Cite this

@article{ba958aab19764ba8a865eaa539c88966,
title = "Structure of Staphylococcus aureus adenylo-succinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery",
abstract = "The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.",
author = "Fyfe, {Paul K.} and Alice Dawson and Hutchison, {Marie Theres} and Scott Cameron and Hunter, {William N.}",
year = "2010",
month = "8",
day = "1",
doi = "10.1107/S0907444910020081",
language = "English",
volume = "66",
pages = "881--888",
journal = "Acta Crystallographica Section D: Biological Crystallography",
issn = "0907-4449",
publisher = "International Union of Crystallography",
number = "8",

}

Structure of Staphylococcus aureus adenylo-succinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery. / Fyfe, Paul K.; Dawson, Alice; Hutchison, Marie Theres; Cameron, Scott; Hunter, William N.

In: Acta Crystallographica Section D: Biological Crystallography, Vol. 66, No. 8, 01.08.2010, p. 881-888.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure of Staphylococcus aureus adenylo-succinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery

AU - Fyfe, Paul K.

AU - Dawson, Alice

AU - Hutchison, Marie Theres

AU - Cameron, Scott

AU - Hunter, William N.

PY - 2010/8/1

Y1 - 2010/8/1

N2 - The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

AB - The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogen Staphylococcus aureus in complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival of S. aureus and to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme from Escherichia coli are presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit-subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

U2 - 10.1107/S0907444910020081

DO - 10.1107/S0907444910020081

M3 - Article

C2 - 20693687

AN - SCOPUS:77955445609

VL - 66

SP - 881

EP - 888

JO - Acta Crystallographica Section D: Biological Crystallography

JF - Acta Crystallographica Section D: Biological Crystallography

SN - 0907-4449

IS - 8

ER -