Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors.
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.
Longenecker
Kenton L
KL
Department of Structural Biology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. Kenton.Longenecker@Abbott.com
Stewart
Kent D
KD
Madar
David J
DJ
Jakob
Clarissa G
CG
Fry
Elizabeth H
EH
Wilk
Sherwin
S
Lin
Chun W
CW
Ballaron
Stephen J
SJ
Stashko
Michael A
MA
Lubben
Thomas H
TH
Yong
Hong
H
Pireh
Daisy
D
Pei
Zhonghua
Z
Basha
Fatima
F
Wiedeman
Paul E
PE
von Geldern
Thomas W
TW
Trevillyan
James M
JM
Stoll
Vincent S
VS
D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D019281:Dimerization; D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry; D014961:X-Ray Diffraction
D011994:Recombinant Proteins; D014443:Tyrosine; D052216:Glucagon-Like Peptide 1; D004150:Dipeptidases; D018819:Dipeptidyl Peptidase 4