Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors

Kenton L. Longenecker, Kent D. Stewart, David J. Madar, Clarissa G. Jakob, Elizabeth H. Fry, Sherwin Wilk, Chun W. Lin, Stephen J. Ballaron, Michael A. Stashko, Thomas H. Lubben, Hong Yong, Daisy Pireh, Zhonghua Pei, Fatima Basha, Paul E. Wiedeman, Thomas W. Von Geldern, James M. Trevillyan, Vincent S. Stoll

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques. With a high degree of similarity to structures of human DPP-IV, the active site architecture provides important details for the design of inhibitory compounds, and structures of inhibitor-protein complexes offer detailed insight into three-dimensional structure-activity relationships that include a conformational change of Tyr548. Such accommodation is exemplified by the response to chemical substitution on 2-cyanopyrrolidine inhibitors at the 5 position, which conveys inhibitory selectivity for DPP-IV over closely related homologues. A similar conformational change is also observed in the complex with an unrelated synthetic inhibitor containing a xanthine core that is also selective for DPP-IV. These results suggest the conformational flexibility of Tyr548 is unique among protein family members and may be utilized in drug design to achieve peptidase selectivity.

Original languageEnglish
Pages (from-to)7474-7482
Number of pages9
Issue number24
StatePublished - 20 Jun 2006


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