1NWL
Crystal structure of the PTP1B complexed with SP7343-SP7964, a pTyr mimetic
Summary for 1NWL
| Entry DOI | 10.2210/pdb1nwl/pdb |
| Descriptor | protein-tyrosine phosphatase, non-receptor type 1, MAGNESIUM ION, 3-(4-{2-[2-(2-BROMO-ACETYLAMINO)-ETHYLDISULFANYL]-ETHYLCARBAMOYL}-CYCLOHEXYLCARBAMOYL)-PYRAZINE-2-CARBOXYLIC ACID, ... (4 entities in total) |
| Functional Keywords | protein-small molecule inhibitor complex, 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 | 35140.32 |
| Authors | Erlanson, D.A.,McDowell, R.S.,He, M.M.,Randal, M.,Simmons, R.L.,Kung, J.,Waight, A.,Hansen, S. (deposition date: 2003-02-06, release date: 2003-04-01, Last modification date: 2024-02-14) |
| Primary citation | Erlanson, D.A.,McDowell, R.S.,He, M.M.,Randal, M.,Simmons, R.L.,Kung, J.,Waight, A.,Hansen, S. Discovery of a New Phosphotyrosine Mimetic for PTP1B Using Breakaway Tethering J.Am.Chem.Soc., 125:5602-5603, 2003 Cited by PubMed Abstract: Protein tyrosine phosphatases play important roles in many signaling cascades involved in human disease. The identification of druglike inhibitors for these targets is a major challenge, and the discovery of suitable phosphotyrosine (pY) mimetics remains one of the key difficulties. Here we describe an extension of tethering technology, "breakaway tethering", which is ideally suited for discovering such new chemical entities. The approach involves first irreversibly modifying a protein with an extender that contains both a masked thiol and a known pY mimetic. The extender is then cleaved to release the pY mimetic, unmasking the thiol. The resulting protein is screened against a library of disulfide-containing small molecule fragments; any molecules with inherent affinity for the pY binding site will preferentially form disulfides with the extender, allowing for their identification by mass spectrometry. The ability to start from a known substrate mimimizes perturbation of protein structure and increases the opportunity to probe the active site using tethering. We applied this approach to the anti-diabetic protein PTP1B to discover a pY mimetic which belongs to a new molecular class and which binds in a novel fashion. PubMed: 12733877DOI: 10.1021/ja034440c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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