3g0c: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3g0c]] is a 4 chain structure with 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=3G0C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3G0C FirstGlance]. <br>
<table><tr><td colspan='2'>[[3g0c]] is a 4 chain structure with 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=3G0C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3G0C FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RUF:7-(2-CHLOROBENZYL)-1,3-DIMETHYL-8-PIPERAZIN-1-YL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE'>RUF</scene><br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RUF:7-(2-CHLOROBENZYL)-1,3-DIMETHYL-8-PIPERAZIN-1-YL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE'>RUF</scene></td></tr>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g0b|3g0b]], [[3g0d|3g0d]], [[3g0g|3g0g]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g0b|3g0b]], [[3g0d|3g0d]], [[3g0g|3g0g]]</td></tr>
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADCP2, CD26, DPP4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADCP2, CD26, DPP4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3g0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3g0c RCSB], [http://www.ebi.ac.uk/pdbsum/3g0c PDBsum]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3g0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3g0c RCSB], [http://www.ebi.ac.uk/pdbsum/3g0c PDBsum]</span></td></tr>
<table>
</table>
== Function ==
[[http://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> 
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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[[Category: Dipeptidyl-peptidase IV]]
[[Category: Dipeptidyl-peptidase IV]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Aertgeerts, K.]]
[[Category: Aertgeerts, K]]
[[Category: Feng, J.]]
[[Category: Feng, J]]
[[Category: Gwaltney, S L.]]
[[Category: Gwaltney, S L]]
[[Category: Jennings, A.]]
[[Category: Jennings, A]]
[[Category: Kaldor, S W.]]
[[Category: Kaldor, S W]]
[[Category: Kassel, D.]]
[[Category: Kassel, D]]
[[Category: Lee, B.]]
[[Category: Lee, B]]
[[Category: Shi, L.]]
[[Category: Shi, L]]
[[Category: Skene, R J.]]
[[Category: Skene, R J]]
[[Category: Stafford, J A.]]
[[Category: Stafford, J A]]
[[Category: Wallace, M B.]]
[[Category: Wallace, M B]]
[[Category: Webb, D R.]]
[[Category: Webb, D R]]
[[Category: Xu, R.]]
[[Category: Xu, R]]
[[Category: Zhang, Z.]]
[[Category: Zhang, Z]]
[[Category: Aminopeptidase]]
[[Category: Aminopeptidase]]
[[Category: Cell membrane]]
[[Category: Cell membrane]]

Revision as of 19:28, 25 December 2014

Crystal structure of dipeptidyl peptidase IV in complex with a pyrimidinedione inhibitor 1Crystal structure of dipeptidyl peptidase IV in complex with a pyrimidinedione inhibitor 1

Structural highlights

3g0c is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:ADCP2, CD26, DPP4 (Homo sapiens)
Activity:Dipeptidyl-peptidase IV, with EC number 3.4.14.5
Resources:FirstGlance, OCA, RCSB, PDBsum

Function

[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.[1] [2] [3] [4] [5] [6] [7] [8] [9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV.,Zhang Z, Wallace MB, Feng J, Stafford JA, Skene RJ, Shi L, Lee B, Aertgeerts K, Jennings A, Xu R, Kassel DB, Kaldor SW, Navre M, Webb DR, Gwaltney SL J Med Chem. 2010 Dec 27. PMID:21186796[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Durinx C, Lambeir AM, Bosmans E, Falmagne JB, Berghmans R, Haemers A, Scharpe S, De Meester I. Molecular characterization of dipeptidyl peptidase activity in serum: soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur J Biochem. 2000 Sep;267(17):5608-13. PMID:10951221
  2. ↑ Davoodi J, Kelly J, Gendron NH, MacKenzie AE. The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26. Proteomics. 2007 Jun;7(13):2300-10. PMID:17549790 doi:10.1002/pmic.200600654
  3. ↑ Abbott CA, McCaughan GW, Gorrell MD. Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity. FEBS Lett. 1999 Sep 24;458(3):278-84. PMID:10570924
  4. ↑ Ikushima H, Munakata Y, Ishii T, Iwata S, Terashima M, Tanaka H, Schlossman SF, Morimoto C. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8439-44. PMID:10900005
  5. ↑ Gines S, Marino M, Mallol J, Canela EI, Morimoto C, Callebaut C, Hovanessian A, Casado V, Lluis C, Franco R. Regulation of epithelial and lymphocyte cell adhesion by adenosine deaminase-CD26 interaction. Biochem J. 2002 Jan 15;361(Pt 2):203-9. PMID:11772392
  6. ↑ Aertgeerts K, Ye S, Shi L, Prasad SG, Witmer D, Chi E, Sang BC, Wijnands RA, Webb DR, Swanson RV. N-linked glycosylation of dipeptidyl peptidase IV (CD26): effects on enzyme activity, homodimer formation, and adenosine deaminase binding. Protein Sci. 2004 Jan;13(1):145-54. PMID:14691230 doi:10.1110/ps.03352504
  7. ↑ Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen WT. The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res. 2006 May 1;66(9):4652-61. PMID:16651416 doi:10.1158/0008-5472.CAN-05-1245
  8. ↑ Ohnuma K, Uchiyama M, Yamochi T, Nishibashi K, Hosono O, Takahashi N, Kina S, Tanaka H, Lin X, Dang NH, Morimoto C. Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1. J Biol Chem. 2007 Mar 30;282(13):10117-31. Epub 2007 Feb 6. PMID:17287217 doi:10.1074/jbc.M609157200
  9. ↑ Shin JW, Jurisic G, Detmar M. Lymphatic-specific expression of dipeptidyl peptidase IV and its dual role in lymphatic endothelial function. Exp Cell Res. 2008 Oct 1;314(16):3048-56. doi: 10.1016/j.yexcr.2008.07.024. Epub , 2008 Aug 3. PMID:18708048 doi:10.1016/j.yexcr.2008.07.024
  10. ↑ Zhang Z, Wallace MB, Feng J, Stafford JA, Skene RJ, Shi L, Lee B, Aertgeerts K, Jennings A, Xu R, Kassel DB, Kaldor SW, Navre M, Webb DR, Gwaltney SL. Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV. J Med Chem. 2010 Dec 27. PMID:21186796 doi:10.1021/jm101016w

3g0c, resolution 2.69Å

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