2AM1

sp protein ligand 1

Summary for 2AM1

• Entry DOI: 10.2210/pdb2am1/pdb
• Related: 2AM2
• Descriptor: UDP-N-acetylmuramoylalanine-D-glutamyl-lysine-D-alanyl-D-alanine ligase, MurF protein, 2,4-DICHLORO-N-(3-CYANO-4,5,6,7-TETRAHYDRO-BENZOTHIOPHEN-2YL)-5-(MORPHOLINE-4-SULFONYL)-BENZAMIDE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: ligase
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 51339.12

Authors

Longenecker, K.L.,Stamper, G.F.,Hajduk, P.J.,Fry, E.H.,Jakob, C.G.,Harlan, J.E.,Edalji, R.,Bartley, D.M.,Walter, K.A.,Solomon, L.R. (deposition date: 2005-08-08, release date: 2006-01-24, Last modification date: 2024-10-30)

Primary citation

Longenecker, K.L.,Stamper, G.F.,Hajduk, P.J.,Fry, E.H.,Jakob, C.G.,Harlan, J.E.,Edalji, R.,Bartley, D.M.,Walter, K.A.,Solomon, L.R.,Holzman, T.F.,Gu, Y.G.,Lerner, C.G.,Beutel, B.A.,Stoll, V.S.
Structure of MurF from Streptococcus pneumoniae co-crystallized with a small molecule inhibitor exhibits interdomain closure
Protein Sci., 14:3039-3047, 2005

PubMed Abstract: In a broad genomics analysis to find novel protein targets for antibiotic discovery, MurF was identified as an essential gene product for Streptococcus pneumonia that catalyzes a critical reaction in the biosynthesis of the peptidoglycan in the formation of the cell wall. Lacking close relatives in mammalian biology, MurF presents attractive characteristics as a potential drug target. Initial screening of the Abbott small-molecule compound collection identified several compounds for further validation as pharmaceutical leads. Here we report the integrated efforts of NMR and X-ray crystallography, which reveal the multidomain structure of a MurF-inhibitor complex in a compact conformation that differs dramatically from related structures. The lead molecule is bound in the substrate-binding region and induces domain closure, suggestive of the domain arrangement for the as yet unobserved transition state conformation for MurF enzymes. The results form a basis for directed optimization of the compound lead by structure-based design to explore the suitability of MurF as a pharmaceutical target.

PubMed: 16322581
DOI: 10.1110/ps.051604805

Experimental method

X-RAY DIFFRACTION (2.5 Å)