2gbg
From Proteopedia
(New page: 200px<br /><applet load="2gbg" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gbg, resolution 3.000Å" /> '''rat DPP-IV with alk...) |
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| - | [[Image:2gbg.gif|left|200px]]<br /><applet load="2gbg" size=" | + | [[Image:2gbg.gif|left|200px]]<br /><applet load="2gbg" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2gbg, resolution 3.000Å" /> | caption="2gbg, resolution 3.000Å" /> | ||
'''rat DPP-IV with alkynyl cyanopyrrolidine #2'''<br /> | '''rat DPP-IV with alkynyl cyanopyrrolidine #2'''<br /> | ||
==Overview== | ==Overview== | ||
| - | 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 | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2GBG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with SO4 and 1AD as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dipeptidyl-peptidase_IV Dipeptidyl-peptidase IV], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.14.5 3.4.14.5] Full crystallographic information is available from [http:// | + | 2GBG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=1AD:'>1AD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dipeptidyl-peptidase_IV Dipeptidyl-peptidase IV], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.14.5 3.4.14.5] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GBG OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fry, E | + | [[Category: Fry, E H.]] |
| - | [[Category: Jakob, C | + | [[Category: Jakob, C G.]] |
| - | [[Category: Longenecker, K | + | [[Category: Longenecker, K L.]] |
[[Category: Wilk, S.]] | [[Category: Wilk, S.]] | ||
[[Category: 1AD]] | [[Category: 1AD]] | ||
| Line 22: | Line 22: | ||
[[Category: serine peptidase beta propeller]] | [[Category: serine peptidase beta propeller]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:30:04 2008'' |
Revision as of 15:30, 21 February 2008
|
rat DPP-IV with alkynyl cyanopyrrolidine #2
Overview
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.
About this Structure
2GBG is a Single protein structure of sequence from Rattus norvegicus with and as ligands. Active as Dipeptidyl-peptidase IV, with EC number 3.4.14.5 Full crystallographic information is available from OCA.
Reference
Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors., Longenecker KL, Stewart KD, Madar DJ, Jakob CG, Fry EH, Wilk S, Lin CW, Ballaron SJ, Stashko MA, Lubben TH, Yong H, Pireh D, Pei Z, Basha F, Wiedeman PE, von Geldern TW, Trevillyan JM, Stoll VS, Biochemistry. 2006 Jun 20;45(24):7474-82. PMID:16768443
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