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Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog

Nature Structural Biology volume 10, pages 19–25 (2003)Cite this article

Abstract

Dipeptidyl peptidase IV (DPP-IV/CD26) is a multifunctional type II transmembrane serine peptidase. This enzyme contributes to the regulation of various physiological processes, including blood sugar homeostasis, by cleaving peptide hormones, chemokines and neuropeptides. We have determined the 2.5 Å structure of the extracellular region of DPP-IV in complex with the inhibitor valine-pyrrolidide. The catalytic site is located in a large cavity formed between the α/β-hydrolase domain and an eight-bladed β-propeller domain. Both domains participate in inhibitor binding. The structure indicates how substrate specificity is achieved and reveals a new and unexpected opening to the active site.

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Figure 1: Structure of DPP-IV.
Figure 2: Structural comparison of DPP-IV and POP.
Figure 3: Secondary structure of DPP-IV shown over the amino acid sequence.
Figure 4: Active site of DPP-IV.

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Acknowledgements

We thank P.F. Nielsen for MALDI-MS analysis, L. Thim for N-terminal amino acid sequencing and S. Kaltoft, B.B. Knudsen, L.L. Nilausen Schmidt and B. Rosenberg for technical assistance. L. Gordon is thanked for help during data collection at ESRF and L.F. Iversen, S.E. Bjørn, A. Kanstrup and R.D. Carr for fruitful discussions and comments on the manuscript.

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Author notes

  1. Finn C. Wiberg

    Present address: Symphogen A/S, Elektrovej building 375, 2800, Lyngby, Denmark

Authors and Affiliations

  1. Protein Chemistry, Research and Development, Novo Nordisk A/S, Novo Allé, Bagsvaerd, DK-2880, Denmark

    Hanne B. Rasmussen & Sven Branner

  2. Biotechnology, Research and Development, Novo Nordisk A/S, Novo Allé, Bagsvaerd, DK-2880, Denmark

    Finn C. Wiberg & Nicolai Wagtmann

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  1. Hanne B. Rasmussen
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Correspondence to Hanne B. Rasmussen.

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Rasmussen, H., Branner, S., Wiberg, F. et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Mol Biol 10, 19–25 (2003). https://doi.org/10.1038/nsb882

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