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

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 I...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 109; no. 17; pp. 6525 - 6530
Main Authors Bezerra, Gustavo A., Dobrovetsky, Elena, Viertlmayr, Roland, Dong, Aiping, Binter, Alexandra, Abramić, Marija, Macheroux, Peter, Dhe-Paganon, Sirano, Gruber, Karl
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 24.04.2012
National Acad Sciences
Subjects
Analgesics
Binding sites
Biological Sciences
Calorimetry
Crystal structure
Crystallography, X-Ray
Crystals
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism
Entropy
Enzymes
Humans
Ligands
Models, Molecular
Molecular structure
Molecules
Oligopeptides - chemistry
Oligopeptides - metabolism
Opioid peptides
Opioid Peptides - chemistry
Opioid Peptides - metabolism
Pain
Peptides
Protein Binding
Protein Conformation
Thermodynamics
Zinc
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Summary: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.
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Author contributions: G.A.B., M.A., P.M., S.D.-P., and K.G. designed research; G.A.B., E.D., R.V., A.D., and A.B. performed research; G.A.B., A.D., M.A., P.M., S.D.-P., and K.G. analyzed data; and G.A.B., M.A., P.M., S.D.-P., and K.G. wrote the paper.
Edited by William W. Bachovchin, Tufts University School of Medicine, Boston, MA, and accepted by the Editorial Board March 9, 2012 (received for review November 2, 2011)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1118005109