2GBC

Native DPP-IV (CD26) from Rat

Summary for 2GBC

• Entry DOI: 10.2210/pdb2gbc/pdb
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: beta propeller, hydrolase
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 2
• Total formula weight: 170887.24

Authors

Longenecker, K.L.,Jakob, C.G.,Fry, E.H.,Wilk, S. (deposition date: 2006-03-10, release date: 2006-07-04, Last modification date: 2024-11-20)

Primary citation

Longenecker, K.L.,Stewart, K.D.,Madar, D.J.,Jakob, C.G.,Fry, E.H.,Wilk, S.,Lin, C.W.,Ballaron, S.J.,Stashko, M.A.,Lubben, T.H.,Yong, H.,Pireh, D.,Pei, Z.,Basha, F.,Wiedeman, P.E.,Von Geldern, T.W.,Trevillyan, J.M.,Stoll, V.S.
Crystal Structures of DPP-IV (CD26) from Rat Kidney Exhibit Flexible Accommodation of Peptidase-Selective Inhibitors.
Biochemistry, 45:7474-7482, 2006

PubMed Abstract: 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.

PubMed: 16768443
DOI: 10.1021/bi060184f

Experimental method

X-RAY DIFFRACTION (2.8 Å)