2iit: Difference between revisions

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[[Image:2iit.gif|left|200px]]<br /><applet load="2iit" size="350" color="white" frame="true" align="right" spinBox="true"
[[Image:2iit.gif|left|200px]]
caption="2iit, resolution 2.35&Aring;" />
 
'''Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor'''<br />
{{Structure
|PDB= 2iit |SIZE=350|CAPTION= <scene name='initialview01'>2iit</scene>, resolution 2.35&Aring;
|SITE=
|LIGAND= <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene> and <scene name='pdbligand=872:(3R)-4-[(3R)-3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)BUTANOYL]-3-(2,2,2-TRIFLUOROETHYL)-1,4-DIAZEPAN-2-ONE'>872</scene>
|ACTIVITY= [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]
|GENE= DPP4, ADCP2, CD26 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
}}
 
'''Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor'''
 


==Overview==
==Overview==
Line 7: Line 16:


==About this Structure==
==About this Structure==
2IIT 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=NAG:'>NAG</scene>, <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=872:'>872</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=2IIT OCA].  
2IIT is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IIT OCA].  


==Reference==
==Reference==
(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoro ethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes., Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Scapin G, Patel S, Gao YD, Singh S, Wu J, Zhang X, Thornberry NA, Weber AE, Bioorg Med Chem Lett. 2007 Jan 1;17(1):49-52. Epub 2006 Oct 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17055272 17055272]
(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoro ethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes., Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Scapin G, Patel S, Gao YD, Singh S, Wu J, Zhang X, Thornberry NA, Weber AE, Bioorg Med Chem Lett. 2007 Jan 1;17(1):49-52. Epub 2006 Oct 5. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17055272 17055272]
[[Category: Dipeptidyl-peptidase IV]]
[[Category: Dipeptidyl-peptidase IV]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
Line 22: Line 31:
[[Category: hydrolase; alpha/beta; beta-propeller; dimer]]
[[Category: hydrolase; alpha/beta; beta-propeller; dimer]]


''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:53:08 2008''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:30:11 2008''

Revision as of 15:30, 20 March 2008

File:2iit.gif


Drag the structure with the mouse to rotate
2iit, resolution 2.35Å
Ligands: NAG, NA and 872
Gene: DPP4, ADCP2, CD26 (Homo sapiens)
Activity: Dipeptidyl-peptidase IV, with EC number 3.4.14.5
Coordinates: save as pdb, mmCIF, xml



Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor


Overview

Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.

About this Structure

2IIT is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoro ethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes., Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Scapin G, Patel S, Gao YD, Singh S, Wu J, Zhang X, Thornberry NA, Weber AE, Bioorg Med Chem Lett. 2007 Jan 1;17(1):49-52. Epub 2006 Oct 5. PMID:17055272

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