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
AN - SCOPUS:84978966687
SN - 0969-2126
VL - 24
SP - 1282
EP - 1291
JO - Structure
JF - Structure
IS - 8
ER -