3sx4
From Proteopedia
Crystal structure of human dpp-iv in complex with sa-(+)-3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyphenyl)- 2-methyl-5h-pyrrolo[3,4-b]pyridin-7(6h)-one
Structural highlights
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 PubMedDesign, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37nM, 2.2, and 5.7muM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10mumol/kg in ob/ob mice. 7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site.,Wang W, Devasthale P, Wang A, Harrity T, Egan D, Morgan N, Cap M, Fura A, Klei HE, Kish K, Weigelt C, Sun L, Levesque P, Li YX, Zahler R, Kirby MS, Hamann LG Bioorg Med Chem Lett. 2011 Nov 15;21(22):6646-51. Epub 2011 Sep 24. PMID:21996520[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Dipeptidyl-peptidase IV | Human | Large Structures | Klei, H E | Alpha/beta hydrolase fold | Aminopeptidase | Beta barrel | Beta propeller | Dimer | Dpp4 | Exopeptidase | Glycoprotein | Hydrolase-hydrolase inhibitor complex | Membrane | Protease | Protein:inhibitor complex | Secreted | Serine protease | Signal- anchor | Transmembrane
