Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III
| Autor: | Karl Gruber, Sirano Dhe-Paganon, Alexandra Binter, Roland Viertlmayr, Peter Macheroux, Gustavo Arruda Bezerra, Elena Dobrovetsky, Marija Abramić, Aiping Dong |
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| Rok vydání: | 2012 |
| Předmět: |
chemistry.chemical_classification
Models Molecular Oligopeptide Multidisciplinary Chemistry Protein Conformation Entropy Isothermal titration calorimetry Peptide binding Plasma protein binding Calorimetry Biological Sciences Crystallography X-Ray Ligands Protein structure Enzyme Biochemistry Opioid Peptides Hydrolase Humans Opioid peptide isothermal titration calorimetry metallopeptidase peptide binding X-ray crystallography Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Oligopeptides Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 109(17) |
| ISSN: | 1091-6490 |
| Popis: | Opioid peptides are involved in various essential physiological processes, most notably nociception. Dipeptidyl peptidase III (DPP III) is one of the most important enkephalin-degrading enzymes associated with the mammalian pain modulatory system. Here we describe the X-ray structures of human DPP III and its complex with the opioid peptide tynorphin, which rationalize the enzyme's substrate specificity and reveal an exceptionally large domain motion upon ligand binding. Microcalorimetric analyses point at an entropy-dominated process, with the release of water molecules from the binding cleft (“entropy reservoir”) as the major thermodynamic driving force. Our results provide the basis for the design of specific inhibitors that enable the elucidation of the exact role of DPP III and the exploration of its potential as a target of pain intervention strategies. |
| Databáze: | OpenAIRE |
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