2UUP

Crystal structure of MurD ligase in complex with D-Glu containing sulfonamide inhibitor

Summary for 2UUP

• Entry DOI: 10.2210/pdb2uup/pdb
• Related: 1E0D 1EEH 1UAG 2JFF 2JFG 2JFH 2UAG 2UUO 3UAG 4UAG
• Descriptor: UDP-N-ACETYLMURAMOYLALANINE--D-GLUTAMATE LIGASE, N-({6-[(4-CYANOBENZYL)OXY]NAPHTHALEN-2-YL}SULFONYL)-D-GLUTAMIC ACID, SULFATE ION, ... (4 entities in total)
• Functional Keywords: murd-inhibitor complex, peptidoglycan synthesis, ligase, cell wall, cell shape, cell cycle, nucleotide-binding, sulfonamide inhibitor, murd ligase, atp-binding, cell division
• Biological source: ESCHERICHIA COLI
• Total number of polymer chains: 1
• Total formula weight: 48736.07

Authors

Humljan, J.,Kotnik, M.,Contreras-Martel, C.,Blanot, D.,Urleb, U.,Dessen, A.,Solmajer, T.,Gobec, S. (deposition date: 2007-03-06, release date: 2008-03-25, Last modification date: 2023-12-13)

Primary citation

Humljan, J.,Kotnik, M.,Contreras-Martel, C.,Blanot, D.,Urleb, U.,Dessen, A.,Solmajer, T.,Gobec, S.
Novel naphthalene-N-sulfonyl-D-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis enzyme.
J. Med. Chem., 51:7486-7494, 2008

PubMed Abstract: Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships.The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transition state analogues, displayed IC50 values ranging from 80 to 600 microM. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.

PubMed: 19007109
DOI: 10.1021/jm800762u

Experimental method

X-RAY DIFFRACTION (1.88 Å)