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2g5t

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Revision as of 07:48, 18 October 2017

Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ag

Structural highlights

2g5t is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2g5p
Gene:	DPP4, ADCP2, CD26 (HUMAN)
Activity:	Dipeptidyl-peptidase IV, with EC number 3.4.14.5
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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.

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^[10]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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. Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors. J Med Chem. 2006 Jun 15;49(12):3520-35. PMID:16759095 doi:10.1021/jm051283e

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2g5t"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ag==
 <StructureSection load='2g5t' size='340' side='right' caption='[[2g5t]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DPP4, ADCP2, CD26 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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 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=2g5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g5t OCA], [http://pdbe.org/2g5t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2g5t RCSB], [http://www.ebi.ac.uk/pdbsum/2g5t 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=2g5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g5t OCA], [http://pdbe.org/2g5t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2g5t RCSB], [http://www.ebi.ac.uk/pdbsum/2g5t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2g5t ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 30: / Line 31: @@
 </div>
 <div class="pdbe-citations 2g5t" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Dipeptidyl peptidase|Dipeptidyl peptidase]]
 == References ==
 <references/>

2g5t

From Proteopedia

Revision as of 07:48, 18 October 2017

Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ag

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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