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: Gustavo A Bezerra, Elena Dobrovetsky, Roland Viertlmayr, Aiping Dong, Alexandra Binter, Marija Abramic, Peter Macheroux, Sirano Dhe-Paganon, Karl Gruber
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 17 Pg. 6525-30 (Apr 24 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22493238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Oligopeptides
• Opioid Peptides
• tynorphin
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• dipeptidyl peptidase III

Topics

• Calorimetry
• Crystallography, X-Ray
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (chemistry, metabolism)
• Entropy
• Humans
• Ligands
• Models, Molecular
• Oligopeptides (chemistry, metabolism)
• Opioid Peptides (chemistry, metabolism)
• Protein Binding
• Protein Conformation