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

20 Citations (Scopus)

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

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