1NL9
Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Compound 12 Using a Linked-Fragment Strategy
Summary for 1NL9
Entry DOI | 10.2210/pdb1nl9/pdb |
Related | 1NNY 1NO6 |
Descriptor | Protein-tyrosine phosphatase, non-receptor type 1, 2-{[4-(2-ACETYLAMINO-2-PENTYLCARBAMOYL-ETHYL)-NAPHTHALEN-1-YL]-OXALYL-AMINO}-BENZOIC ACID (3 entities in total) |
Functional Keywords | protein tyrosine phosphatase fold, dual-site oxamic acid inhibitor bound to p-loop, hydrolase |
Biological source | Homo sapiens (human) |
Cellular location | Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031 |
Total number of polymer chains | 1 |
Total formula weight | 37899.21 |
Authors | Szczepankiewicz, B.G.,Liu, G.,Hajduk, P.J.,Abad-Zapatero, C.,Pei, Z.,Xin, Z.,Lubben, T.,Trevillyan, J.M.,Stashko, M.A.,Ballaron, S.J.,Liang, H.,Huang, F.,Hutchins, C.W.,Fesik, S.W.,Jirousek, M.R. (deposition date: 2003-01-06, release date: 2003-04-08, Last modification date: 2023-08-16) |
Primary citation | Szczepankiewicz, B.G.,Liu, G.,Hajduk, P.J.,Abad-Zapatero, C.,Pei, Z.,Xin, Z.,Lubben, T.,Trevillyan, J.M.,Stashko, M.A.,Ballaron, S.J.,Liang, H.,Huang, F.,Hutchins, C.W.,Fesik, S.W.,Jirousek, M.R. Discovery of a Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy J.Am.Chem.Soc., 125:4087-4096, 2003 Cited by PubMed Abstract: 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. PubMed: 12670229DOI: 10.1021/ja0296733 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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