5KBY

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

Summary for 5KBY

• Entry DOI: 10.2210/pdb5kby/pdb
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: peptidase, glp-1, metabolic disease, co-complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 350397.83

Authors

Skene, R.J.,Jennings, A.J. (deposition date: 2016-06-03, release date: 2016-07-13, Last modification date: 2024-12-25)

Primary citation

Grimshaw, C.E.,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, 11:e0157509-e0157509, 2016

PubMed Abstract: 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 ≈ 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.

PubMed: 27328054
DOI: 10.1371/journal.pone.0157509

Experimental method

X-RAY DIFFRACTION (2.24 Å)