Crystallographic Analysis of Bacterial Signal Peptidase in Ternary Complex with Arylomycin A2 and a β-Sultam Inhibitor
| Autor: | Malcolm G. P. Page, Jürg Dreier, Patrick Roussel, Chuanyun Luo, Mark Paetzel |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Serine Proteinase Inhibitors Macromolecular Substances Stereochemistry Static Electricity Crystal structure Crystallography X-Ray medicine.disease_cause Biochemistry chemistry.chemical_compound Catalytic Domain medicine Arylomycin A2 Binding site Escherichia coli Ternary complex Sulfonamides Signal peptidase Molecular Structure Chemistry Escherichia coli Proteins Serine Endopeptidases Membrane Proteins Peptide Fragments Endopeptidase Kinetics Crystallography Oligopeptides Derivative (chemistry) |
| Zdroj: | Biochemistry. 48:8976-8984 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi9009538 |
| Popis: | Bacterial type I signal peptidase (SPase I), an essential membrane-bound endopeptidase with a unique Ser/Lys dyad mechanism, is being investigated as a potential novel antibiotic target. We present here binding and inhibition assays along with crystallographic data that shows that the lipohexapeptide-based natural product arylomycin A2 and the morpholino-beta-sultam derivative (BAL0019193) inhibit SPase I by binding to non-overlapping subsites near the catalytic center. The 2.0 A resolution crystal structure of the soluble catalytic domain of Escherichia coli SPase I (SPase I Delta2-75) in ternary complex with arylomycin A2 and BAL0019193 reveals the position of BAL0019193 adjacent to arylomycin A2 within the SPase I binding site. BAL0019193 binds in a noncovalent manner in close proximity to SPase I residues Ser88, Ser90, Lys145, Asn277, Ala279, and Glu307, as well as atom O45 of arylomycin A2. The binding mode of arylomycin A2 in this 2.0 A resolution ternary complex is compared to that seen in the previous 2.5 A resolution arylomycin A2-SPase cocrystal structure. This work contributes to our understanding of SPase I inhibitor/substrate recognition and should prove helpful in the further development of novel antibiotics based on the inhibition of SPase I. |
| Databáze: | OpenAIRE |
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