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| {{STRUCTURE_2gbf| PDB=2gbf | SCENE= }} | | {{STRUCTURE_2gbf| PDB=2gbf | SCENE= }} |
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| '''rat dpp-IV with alkynyl cyanopyrrolidine #1'''
| | ===rat dpp-IV with alkynyl cyanopyrrolidine #1=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16768443}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16768443 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16768443}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Wilk, S.]] | | [[Category: Wilk, S.]] |
| [[Category: Serine peptidase beta propeller]] | | [[Category: Serine peptidase beta propeller]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:54:48 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 15:45:45 2008'' |
