2g5p
From Proteopedia
(New page: 200px<br /> <applet load="2g5p" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g5p, resolution 2.400Å" /> '''Crystal structure ...) |
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| - | [[Image:2g5p.gif|left|200px]]<br /> | + | [[Image:2g5p.gif|left|200px]]<br /><applet load="2g5p" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2g5p, resolution 2.400Å" /> | caption="2g5p, resolution 2.400Å" /> | ||
'''Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ac'''<br /> | '''Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ac'''<br /> | ||
==Overview== | ==Overview== | ||
| - | A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine | + | A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats. |
==About this Structure== | ==About this Structure== | ||
| - | 2G5P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ADF as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 2G5P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ADF:'>ADF</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=2G5P OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fry, E | + | [[Category: Fry, E H.]] |
| - | [[Category: Lake, M | + | [[Category: Lake, M R.]] |
[[Category: Li, X.]] | [[Category: Li, X.]] | ||
| - | [[Category: Longenecker, K | + | [[Category: Longenecker, K L.]] |
[[Category: Pei, Z.]] | [[Category: Pei, Z.]] | ||
| - | [[Category: Solomon, L | + | [[Category: Solomon, L R.]] |
[[Category: ADF]] | [[Category: ADF]] | ||
[[Category: beta-propeller]] | [[Category: beta-propeller]] | ||
[[Category: serine peptidase]] | [[Category: serine peptidase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:28:26 2008'' |
Revision as of 15:28, 21 February 2008
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Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ac
Overview
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
About this Structure
2G5P is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Dipeptidyl-peptidase IV, with EC number 3.4.14.5 Full crystallographic information is available from OCA.
Reference
Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors., Pei Z, Li X, Longenecker K, von Geldern TW, Wiedeman PE, Lubben TH, Zinker BA, Stewart K, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Long M, Wells H, Kempf-Grote AJ, Madar DJ, McDermott TS, Bhagavatula L, Fickes MG, Pireh D, Solomon LR, Lake MR, Edalji R, Fry EH, Sham HL, Trevillyan JM, J Med Chem. 2006 Jun 15;49(12):3520-35. PMID:16759095
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