Structural studies of Streptococcus pneumoniae EPSP synthase in unliganded state, tetrahedral intermediate-bound state and S3P-GLP-bound state.
The shikimate pathway synthesizes aromatic amino acids and other essential metabolites that are necessary for bacteria, plants and fungi to survive. This pathway is not present in vertebrates and therefore represents an attractive target for antibacterial agents. We have successfully crystallized and solved the structure of unliganded, inhibitor-liganded and tetrahedral intermediate (TI)-liganded forms of Streptococcus pneumoniae EPSP synthase. The overall topology of the S. pneumoniae EPSP synthase is similar to that of the Escherichia coli EPSP synthase. In addition, the majority of residues responsible for ligand binding were conserved between the two proteins. TI-liganded structure provides absolute configuration of the C-2 atom from the F-PEP moiety of the enzyme-bound intermediate and also defines key residues responsible for the enzyme reaction. Comparison of the unliganded state and substrate-bound state of the enzyme provides insights into the structural mechanisms involved in dynamic events of ligand binding, domain movement and closure. This structural study of the pathogenic bacteria S. pneumoniae EPSP synthase with inhibitor and TI will provide invaluable information for the design of new-generation antibiotics.
Park
HaJeung
H
School of Molecular Biosciences, Washington State University, Pullman 99164, USA.
Hilsenbeck
Jacqueline L
JL
Kim
Hak Jun
HJ
Shuttleworth
Wendy A
WA
Park
Yong Ho
YH
Evans
Jeremy N
JN
Kang
ChulHee
C
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D019883:Alkyl and Aryl Transferases / Q000737:chemistry* / Q000378:metabolism*; D020816:Amino Acid Motifs; D018360:Crystallography, X-Ray; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008970:Molecular Weight; D010728:Phosphoenolpyruvate / Q000378:metabolism; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012765:Shikimic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D000097797:Glyphosate
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D019883:Alkyl and Aryl Transferases; D005998:Glycine; D008024:Ligands; D010728:Phosphoenolpyruvate; D012765:Shikimic Acid; D000097797:Glyphosate; C042786:shikimic acid-3-phosphate