Structure of MurF from Streptococcus pneumoniae co-crystallized with a small molecule inhibitor exhibits interdomain closure.
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.
Longenecker
Kenton L
KL
Department of Structural Biology, R46Y, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Kenton.Longenecker@Abbott.com
Stamper
Geoffrey F
GF
Hajduk
Philip J
PJ
Fry
Elizabeth H
EH
Jakob
Clarissa G
CG
Harlan
John E
JE
Edalji
Rohinton
R
Bartley
Diane M
DM
Walter
Karl A
KA
Solomon
Larry R
LR
Holzman
Thomas F
TF
Gu
Yu Gui
YG
Lerner
Claude G
CG
Beutel
Bruce A
BA
Stoll
Vincent S
VS
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017385:Sequence Homology; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D008024:Ligands; D010453:Peptide Synthases; C060628:UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase