View source for 2oae


==Crystal structure of rat dipeptidyl peptidase (DPPIV) with thiazole-based peptide mimetic #31==
<StructureSection load='2oae' size='340' side='right'caption='[[2oae]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2oae]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OAE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OAE 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]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AIL:N-{[(3S,5S)-5-(1,3-THIAZOLIDIN-3-YLCARBONYL)PYRROLIDIN-3-YL]METHYL}-1,3-THIAZOLE-4-CARBOXAMIDE'>AIL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2oae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oae OCA], [https://pdbe.org/2oae PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2oae RCSB], [https://www.ebi.ac.uk/pdbsum/2oae PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2oae ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DPP4_RAT DPP4_RAT] 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 (By similarity). Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/oa/2oae_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2oae ConSurf].
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== Publication Abstract from PubMed ==
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a &gt;400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.

Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.,Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM Bioorg Med Chem Lett. 2007 Apr 1;17(7):2005-12. Epub 2007 Jan 19. PMID:17276063<ref>PMID:17276063</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2oae" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dipeptidyl peptidase 3D structures|Dipeptidyl peptidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Longenecker KL]]
[[Category: Patel J]]
[[Category: Shuai Q]]
[[Category: Wiedeman P]]