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