Creation of a S1P Lyase bacterial surrogate for structure-based drug design
| Autor: | Grier A. Wallace, Elzbieta Radziejewska, Susan C. Marchie, Jürgen Dinges, Kara L. Queeney, Charles W. Hutchins, David Banach, Christopher M. Harris, Eric Dominguez, Russell A. Judge, Maria A. Argiriadi, Jennifer DiMauro |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Mutant Pharmaceutical Science Crystallography X-Ray 01 natural sciences Biochemistry 03 medical and health sciences Drug Discovery Escherichia coli Homology modeling Site-directed mutagenesis Molecular Biology Aldehyde-Lyases chemistry.chemical_classification 010405 organic chemistry Chemistry Organic Chemistry Symbiobacterium thermophilum Lyase Small molecule 0104 chemical sciences 030104 developmental biology Enzyme Structural biology Drug Design Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:2293-2296 |
| ISSN: | 0960-894X |
| Popis: | S1P Lyase (SPL) has been described as a drug target in the treatment of autoimmune diseases. It plays an important role in maintaining intracellular levels of S1P thereby affecting T cell egress from lymphoid tissues. Several groups have already published approaches to inhibit S1P Lyase with small molecules, which in turn increase endogenous S1P concentrations resulting in immunosuppression. The use of structural biology has previously aided SPL inhibitor design. Novel construct design is at times necessary to provide a reagent for protein crystallography. Here we present a chimeric bacterial protein scaffold used for protein X-ray structures in the presence of early small molecule inhibitors. Mutations were introduced to the bacterial SPL from Symbiobacterium thermophilum which mimic the human enzyme. As a result, two mutant StSPL crystal structures resolved to 2.8Å and 2.2Å resolutions were solved and provide initial structural hypotheses for an isoxazole chemical series, whose optimization is discussed in the accompanying paper. |
| Databáze: | OpenAIRE |
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