3OPM

Crystal Structure of Human DPP4 Bound to TAK-294

Summary for 3OPM

• Entry DOI: 10.2210/pdb3opm/pdb
• Related: 3O95 3O9V
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-{[3-(aminomethyl)-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl]oxy}acetamide, ... (5 entities in total)
• Functional Keywords: protease and 8-bladed beta-propeller domain, aminopeptidase, cell membrane, glycoprotein, hydrolase, membrane, protease, secreted, serine protease, signal-anchor, transmembrane, signaling protein, hydrolase-hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 348364.11

Authors

Yano, J.K.,Aertgeerts, K. (deposition date: 2010-09-01, release date: 2011-10-19, Last modification date: 2024-10-16)

Primary citation

Banno, Y.,Miyamoto, Y.,Sasaki, M.,Oi, S.,Asakawa, T.,Kataoka, O.,Takeuchi, K.,Suzuki, N.,Ikedo, K.,Kosaka, T.,Tsubotani, S.,Tani, A.,Funami, M.,Tawada, M.,Yamamoto, Y.,Aertgeerts, K.,Yano, J.,Maezaki, H.
Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: a new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554.
Bioorg.Med.Chem., 19:4953-4970, 2011

PubMed Abstract: The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors.

PubMed: 21764322
DOI: 10.1016/j.bmc.2011.06.059

Experimental method

X-RAY DIFFRACTION (2.72 Å)