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National Academy of Sciences, Proceedings of the National Academy of Sciences, 17(109), p. 6525-6530, 2012

DOI: 10.1073/pnas.1118005109

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Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

Journal article published in 2012 by Gustavo A. Bezerra ORCID, Elena Dobrovetsky, Roland Viertlmayr, Aiping Dong, Alexandra Binter, Marija Abramić, Peter Macheroux, Sirano Dhe-Paganon, Karl Gruber ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.