View source for 3vjl


==Crystal structure of human depiptidyl peptidase IV (DPP-4) in complex with a prolylthiazolidine inhibitor #2==
<StructureSection load='3vjl' size='340' side='right'caption='[[3vjl]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3vjl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VJL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VJL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.393&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=W94:[(2S,4S)-4-{4-[1-PHENYL-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-5-YL]PIPERIDIN-1-YL}PYRROLIDIN-2-YL](1,3-THIAZOLIDIN-3-YL)METHANONE'>W94</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3vjl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vjl OCA], [https://pdbe.org/3vjl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vjl RCSB], [https://www.ebi.ac.uk/pdbsum/3vjl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vjl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DPP4_HUMAN DPP4_HUMAN] Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.<ref>PMID:10951221</ref> <ref>PMID:17549790</ref> <ref>PMID:10570924</ref> <ref>PMID:10900005</ref> <ref>PMID:11772392</ref> <ref>PMID:14691230</ref> <ref>PMID:16651416</ref> <ref>PMID:17287217</ref> <ref>PMID:18708048</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the gamma-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl carbonyl]thiazolidine (8g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8g, at 0.03mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.

Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.,Yoshida T, Akahoshi F, Sakashita H, Kitajima H, Nakamura M, Sonda S, Takeuchi M, Tanaka Y, Ueda N, Sekiguchi S, Ishige T, Shima K, Nabeno M, Abe Y, Anabuki J, Soejima A, Yoshida K, Takashina Y, Ishii S, Kiuchi S, Fukuda S, Tsutsumiuchi R, Kosaka K, Murozono T, Nakamaru Y, Utsumi H, Masutomi N, Kishida H, Miyaguchi I, Hayashi Y Bioorg Med Chem. 2012 Oct 1;20(19):5705-19. doi: 10.1016/j.bmc.2012.08.012. Epub , 2012 Aug 17. PMID:22959556<ref>PMID:22959556</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3vjl" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dipeptidyl peptidase 3D structures|Dipeptidyl peptidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Akahoshi F]]
[[Category: Ishii S]]
[[Category: Kishida H]]
[[Category: Miyaguchi I]]
[[Category: Yoshida T]]