Structure of MurF fromStreptococcus pneumoniaeco-crystallized with a small molecule inhibitor exhibits interdomain closure
| Autor: | Kenton L. Longenecker, Karl A. Walter, Rohinton Edalji, John E. Harlan, Diane Bartley, Philip J. Hajduk, Larry R. Solomon, Thomas F. Holzman, Geoffrey F. Stamper, Yu Gui Gu, Vincent S. Stoll, Claude G. Lerner, Bruce A. Beutel, Elizabeth H. Fry, Clarissa G. Jakob |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Molecular Sequence Data Sequence Homology Sequence alignment Biology Crystallography X-Ray Ligands Biochemistry Article Substrate Specificity chemistry.chemical_compound Amino Acid Sequence Enzyme Inhibitors Peptide Synthases Binding site Nuclear Magnetic Resonance Biomolecular Molecular Biology Peptide sequence chemistry.chemical_classification DNA ligase Binding Sites Small molecule Protein Structure Tertiary Streptococcus pneumoniae Enzyme chemistry Essential gene Peptidoglycan Sequence Alignment |
| Zdroj: | Protein Science. 14:3039-3047 |
| ISSN: | 1469-896X 0961-8368 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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