3ZM5

CRYSTAL STRUCTURE OF MURF LIGASE IN COMPLEX WITH CYANOTHIOPHENE INHIBITOR

Summary for 3ZM5

• Entry DOI: 10.2210/pdb3zm5/pdb
• Related: 3ZL8 3ZM6
• Descriptor: UDP-N-ACETYLMURAMOYL-TRIPEPTIDE--D-ALANYL-D-ALANINE LIGASE, 2,4-bis(chloranyl)-N-[3-cyano-6-[(4-hydroxyphenyl)methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-2-yl]-5-morpholin-4-ylsulfonyl-benzamide (3 entities in total)
• Functional Keywords: ligase, peptidoglycan synthesis, adp-forming enzyme, cell wall, cell shape, cell cycle, cell divison, nucleotide-binding, atp-binding
• Biological source: STREPTOCOCCUS PNEUMONIAE R6
• Cellular location: Cytoplasm (By similarity): Q8DNV6
• Total number of polymer chains: 1
• Total formula weight: 52237.94

Authors

Hrast, M.,Turk, S.,Sosic, I.,Knez, D.,Randall, C.P.,Barreteau, H.,Contreras-Martel, C.,Dessen, A.,ONeill, A.J.,Mengin-Lecreulx, D.,Blanot, D.,Gobec, S. (deposition date: 2013-02-05, release date: 2013-07-03, Last modification date: 2023-12-20)

Primary citation

Hrast, M.,Turk, S.,Sosic, I.,Knez, D.,Randall, C.P.,Barreteau, H.,Contreras-Martel, C.,Dessen, A.,O'Neill, A.J.,Mengin-Lecreulx, D.,Blanot, D.,Gobec, S.
Structure-Activity Relationships of New Cyanothiophene Inhibitors of the Essential Peptidoglycan Biosynthesis Enzyme Murf.
Eur.J.Med.Chem., 66C:32-, 2013

PubMed Abstract: Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc-L-Ala-γ-D-Glu-meso-DAP (or L-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization toward effective novel antibacterials.

PubMed: 23786712
DOI: 10.1016/J.EJMECH.2013.05.013

Experimental method

X-RAY DIFFRACTION (2.94 Å)