title: Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III.
abstract: 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.
authors.affiliation: Institute of Molecular Biosciences,  University of Graz, A-8010 Graz,  Austria.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Bezerra
authors.forename: Elena
authors.initials: E
authors.lastname: Dobrovetsky
authors.forename: Roland
authors.initials: R
authors.lastname: Viertlmayr
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Alexandra
authors.initials: A
authors.lastname: Binter
authors.forename: Marija
authors.initials: M
authors.lastname: Abramic
authors.forename: Peter
authors.initials: P
authors.lastname: Macheroux
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.forename: Karl
authors.initials: K
authors.lastname: Gruber
mesh_terms: D002151:Calorimetry; D018360:Crystallography, X-Ray; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry / Q000378:metabolism*; D019277:Entropy; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D008024:Ligands; D009842:Oligopeptides; D018847:Opioid Peptides; C412863:tynorphin; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III