1nl9

File:1nl9.gif

spinqualitylabelsall models 1nl9, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Compound 12 Using a Linked-Fragment Strategy

OverviewOverview

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates, the insulin receptor. Inhibition of PTP1B is expected to improve insulin, action, and the design of small molecule PTP1B inhibitors to treat type II, diabetes has received considerable attention. In this work, NMR-based, screening identified a nonselective competitive inhibitor of PTP1B. A, second site ligand was also identified by NMR-based screening and then, linked to the catalytic site ligand by rational design. X-ray data, confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and, good selectivity over many other phosphatases. The modular approach to, drug design described in this work should be applicable for the design of, potent and selective inhibitors of other therapeutically relevant protein, tyrosine phosphatases.

DiseaseDisease

Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]

About this StructureAbout this Structure

1NL9 is a Single protein structure of sequence from Homo sapiens with 989 as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.

ReferenceReference

Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy., Szczepankiewicz BG, Liu G, Hajduk PJ, Abad-Zapatero C, Pei Z, Xin Z, Lubben TH, Trevillyan JM, Stashko MA, Ballaron SJ, Liang H, Huang F, Hutchins CW, Fesik SW, Jirousek MR, J Am Chem Soc. 2003 Apr 9;125(14):4087-96. PMID:12670229

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