Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target

Tatiana P. Soares da Costa, Sebastien Desbois, Con Dogovski, Michael A. Gorman, Natalia E. Ketaren, Jason J. Paxman, Tanzeela Siddiqui, Leanne M. Zammit, Belinda M. Abbott, Roy M. Robins-Browne, Michael W. Parker, Geoffrey B. Jameson, Nathan E. Hall, Santosh Panjikar, Matthew A. Perugini

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the lysine biosynthesis pathway of bacteria. The pathway can be regulated by feedback inhibition of DHDPS through the allosteric binding of the end product, lysine. The current dogma states that DHDPS from Gram-negative bacteria are inhibited by lysine but orthologs from Gram-positive species are not. The 1.65-Å resolution structure of the Gram-negative Legionella pneumophila DHDPS and the 1.88-Å resolution structure of the Gram-positive Streptococcus pneumoniae DHDPS bound to lysine, together with comprehensive functional analyses, show that this dogma is incorrect. We subsequently employed our crystallographic data with bioinformatics, mutagenesis, enzyme kinetics, and microscale thermophoresis to reveal that lysine-mediated inhibition is not defined by Gram staining, but by the presence of a His or Glu at position 56 (Escherichia coli numbering). This study has unveiled the molecular determinants defining lysine-mediated allosteric inhibition of bacterial DHDPS.

Original languageEnglish
Pages (from-to)1282-1291
Number of pages10
JournalStructure
Volume24
Issue number8
DOIs
Publication statusPublished - 2 Aug 2016

Cite this

Soares da Costa, T. P., Desbois, S., Dogovski, C., Gorman, M. A., Ketaren, N. E., Paxman, J. J., ... Perugini, M. A. (2016). Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target. Structure, 24(8), 1282-1291. https://doi.org/10.1016/j.str.2016.05.019
Soares da Costa, Tatiana P. ; Desbois, Sebastien ; Dogovski, Con ; Gorman, Michael A. ; Ketaren, Natalia E. ; Paxman, Jason J. ; Siddiqui, Tanzeela ; Zammit, Leanne M. ; Abbott, Belinda M. ; Robins-Browne, Roy M. ; Parker, Michael W. ; Jameson, Geoffrey B. ; Hall, Nathan E. ; Panjikar, Santosh ; Perugini, Matthew A. / Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target. In: Structure. 2016 ; Vol. 24, No. 8. pp. 1282-1291.
@article{d94a8e5c01e8435d9ec1eecb0c3b54b9,
title = "Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target",
abstract = "Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the lysine biosynthesis pathway of bacteria. The pathway can be regulated by feedback inhibition of DHDPS through the allosteric binding of the end product, lysine. The current dogma states that DHDPS from Gram-negative bacteria are inhibited by lysine but orthologs from Gram-positive species are not. The 1.65-{\AA} resolution structure of the Gram-negative Legionella pneumophila DHDPS and the 1.88-{\AA} resolution structure of the Gram-positive Streptococcus pneumoniae DHDPS bound to lysine, together with comprehensive functional analyses, show that this dogma is incorrect. We subsequently employed our crystallographic data with bioinformatics, mutagenesis, enzyme kinetics, and microscale thermophoresis to reveal that lysine-mediated inhibition is not defined by Gram staining, but by the presence of a His or Glu at position 56 (Escherichia coli numbering). This study has unveiled the molecular determinants defining lysine-mediated allosteric inhibition of bacterial DHDPS.",
author = "{Soares da Costa}, {Tatiana P.} and Sebastien Desbois and Con Dogovski and Gorman, {Michael A.} and Ketaren, {Natalia E.} and Paxman, {Jason J.} and Tanzeela Siddiqui and Zammit, {Leanne M.} and Abbott, {Belinda M.} and Robins-Browne, {Roy M.} and Parker, {Michael W.} and Jameson, {Geoffrey B.} and Hall, {Nathan E.} and Santosh Panjikar and Perugini, {Matthew A.}",
year = "2016",
month = "8",
day = "2",
doi = "10.1016/j.str.2016.05.019",
language = "English",
volume = "24",
pages = "1282--1291",
journal = "Structure",
issn = "0969-2126",
publisher = "Elsevier",
number = "8",

}

Soares da Costa, TP, Desbois, S, Dogovski, C, Gorman, MA, Ketaren, NE, Paxman, JJ, Siddiqui, T, Zammit, LM, Abbott, BM, Robins-Browne, RM, Parker, MW, Jameson, GB, Hall, NE, Panjikar, S & Perugini, MA 2016, 'Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target' Structure, vol. 24, no. 8, pp. 1282-1291. https://doi.org/10.1016/j.str.2016.05.019

Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target. / Soares da Costa, Tatiana P.; Desbois, Sebastien; Dogovski, Con; Gorman, Michael A.; Ketaren, Natalia E.; Paxman, Jason J.; Siddiqui, Tanzeela; Zammit, Leanne M.; Abbott, Belinda M.; Robins-Browne, Roy M.; Parker, Michael W.; Jameson, Geoffrey B.; Hall, Nathan E.; Panjikar, Santosh; Perugini, Matthew A.

In: Structure, Vol. 24, No. 8, 02.08.2016, p. 1282-1291.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target

AU - Soares da Costa, Tatiana P.

AU - Desbois, Sebastien

AU - Dogovski, Con

AU - Gorman, Michael A.

AU - Ketaren, Natalia E.

AU - Paxman, Jason J.

AU - Siddiqui, Tanzeela

AU - Zammit, Leanne M.

AU - Abbott, Belinda M.

AU - Robins-Browne, Roy M.

AU - Parker, Michael W.

AU - Jameson, Geoffrey B.

AU - Hall, Nathan E.

AU - Panjikar, Santosh

AU - Perugini, Matthew A.

PY - 2016/8/2

Y1 - 2016/8/2

N2 - Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the lysine biosynthesis pathway of bacteria. The pathway can be regulated by feedback inhibition of DHDPS through the allosteric binding of the end product, lysine. The current dogma states that DHDPS from Gram-negative bacteria are inhibited by lysine but orthologs from Gram-positive species are not. The 1.65-Å resolution structure of the Gram-negative Legionella pneumophila DHDPS and the 1.88-Å resolution structure of the Gram-positive Streptococcus pneumoniae DHDPS bound to lysine, together with comprehensive functional analyses, show that this dogma is incorrect. We subsequently employed our crystallographic data with bioinformatics, mutagenesis, enzyme kinetics, and microscale thermophoresis to reveal that lysine-mediated inhibition is not defined by Gram staining, but by the presence of a His or Glu at position 56 (Escherichia coli numbering). This study has unveiled the molecular determinants defining lysine-mediated allosteric inhibition of bacterial DHDPS.

AB - Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the lysine biosynthesis pathway of bacteria. The pathway can be regulated by feedback inhibition of DHDPS through the allosteric binding of the end product, lysine. The current dogma states that DHDPS from Gram-negative bacteria are inhibited by lysine but orthologs from Gram-positive species are not. The 1.65-Å resolution structure of the Gram-negative Legionella pneumophila DHDPS and the 1.88-Å resolution structure of the Gram-positive Streptococcus pneumoniae DHDPS bound to lysine, together with comprehensive functional analyses, show that this dogma is incorrect. We subsequently employed our crystallographic data with bioinformatics, mutagenesis, enzyme kinetics, and microscale thermophoresis to reveal that lysine-mediated inhibition is not defined by Gram staining, but by the presence of a His or Glu at position 56 (Escherichia coli numbering). This study has unveiled the molecular determinants defining lysine-mediated allosteric inhibition of bacterial DHDPS.

UR - http://www.scopus.com/inward/record.url?scp=84978966687&partnerID=8YFLogxK

U2 - 10.1016/j.str.2016.05.019

DO - 10.1016/j.str.2016.05.019

M3 - Article

VL - 24

SP - 1282

EP - 1291

JO - Structure

JF - Structure

SN - 0969-2126

IS - 8

ER -

Soares da Costa TP, Desbois S, Dogovski C, Gorman MA, Ketaren NE, Paxman JJ et al. Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target. Structure. 2016 Aug 2;24(8):1282-1291. https://doi.org/10.1016/j.str.2016.05.019