Potent, multi-target serine protease inhibition achieved by a simplified β-sheet motif
| Autor: | Simon J. de Veer, Joakim E. Swedberg, Maria Brattsand, Darren Leahy, Jessica Van Haeften, Jonathan M. Harris, David E. Hoke, Ashley M. Buckle, Blake T. Riley, Xingchen Chen, Perry J. Hartfield |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular medicine.medical_treatment Amino Acid Motifs Beta sheet Molecular Dynamics Crystallography X-Ray Biochemistry Physical Chemistry 01 natural sciences Serine Computational Chemistry Trypsin Amino Acids Enzyme Inhibitors Materials Plant Proteins 0303 health sciences Crystallography Multidisciplinary 010304 chemical physics biology Organic Compounds Chemistry Physics Biochemistry and Molecular Biology Läkemedelskemi Proteases Condensed Matter Physics Enzymes Physical Sciences Crystal Structure Helianthus Medicine Basic Amino Acids Trypsin Inhibitors Research Article medicine.drug Serine Proteinase Inhibitors Stereochemistry Trypsin inhibitor Science Materials Science Static Electricity Molecular Dynamics Simulation Arginine Crystals Peptides Cyclic 03 medical and health sciences 0103 physical sciences medicine Solid State Physics Animals Protein Interaction Domains and Motifs 030304 developmental biology Serine protease Protease Chemical Bonding Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins Active site Hydrogen Bonding Enzymology biology.protein Cattle Protein Conformation beta-Strand Serine Proteases Medicinal Chemistry Biokemi och molekylärbiologi |
| Zdroj: | PLoS ONE, Vol 14, Iss 1, p e0210842 (2019) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design. |
| Databáze: | OpenAIRE |
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