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5kby

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Revision as of 05:04, 9 September 2016

Crystal structure of dipeptidyl peptidase IV in complex with SYR-472

Structural highlights

5kby is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
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]

Publication Abstract from PubMed

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation approximately 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism.,Grimshaw CE, Jennings A, Kamran R, Ueno H, Nishigaki N, Kosaka T, Tani A, Sano H, Kinugawa Y, Koumura E, Shi L, Takeuchi K PLoS One. 2016 Jun 21;11(6):e0157509. doi: 10.1371/journal.pone.0157509., eCollection 2016. PMID:27328054^[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
↑ Grimshaw CE, Jennings A, Kamran R, Ueno H, Nishigaki N, Kosaka T, Tani A, Sano H, Kinugawa Y, Koumura E, Shi L, Takeuchi K. Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism. PLoS One. 2016 Jun 21;11(6):e0157509. doi: 10.1371/journal.pone.0157509., eCollection 2016. PMID:27328054 doi:http://dx.doi.org/10.1371/journal.pone.0157509

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5kby"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5kby]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KBY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KBY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5AX:2-(ACETYLAMINO)-1,5-ANHYDRO-2-DEOXY-D-GLUCITOL'>5AX</scene>, <scene name='pdbligand=6RL:2-[[6-[(3~{R})-3-AZANYLPIPERIDIN-1-YL]-3-METHYL-2,4-BIS(OXIDANYLIDENE)PYRIMIDIN-1-YL]METHYL]-4-FLUORANYL-BENZENECARBONITRILE'>6RL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6RL:2-[[6-[(3~{R})-3-AZANYLPIPERIDIN-1-YL]-3-METHYL-2,4-BIS(OXIDANYLIDENE)PYRIMIDIN-1-YL]METHYL]-4-FLUORANYL-BENZENECARBONITRILE'>6RL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=5kby FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kby OCA], [http://pdbe.org/5kby PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kby RCSB], [http://www.ebi.ac.uk/pdbsum/5kby PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kby ProSAT]</span></td></tr>

5kby

From Proteopedia

Revision as of 05:04, 9 September 2016

Crystal structure of dipeptidyl peptidase IV in complex with SYR-472

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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