1NWE

Ptp1B R47C Modified at C47 with N-[4-(2-{2-[3-(2-Bromo-acetylamino)-propionylamino]-3-hydroxy-propionylamino}-ethyl)-phenyl]-oxalamic acid

Summary for 1NWE

• Entry DOI: 10.2210/pdb1nwe/pdb
• Descriptor: Protein-tyrosine phosphatase, non-receptor type 1, N-[4-(2-{2-[3-(2-BROMO-ACETYLAMINO)-PROPIONYLAMINO]-3-HYDROXY-PROPIONYLAMINO}-ETHYL)-PHENYL]-OXALAMIC ACID (2 entities in total)
• Functional Keywords: hydrolase, acetylation, phosphorylation, phospatase, phosphotyrosine mimetic
• 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: 35133.74

Authors

Erlanson, D.A.,McDowell, R.S.,He, M.M.,Randal, M.,Simmons, R.L.,Kung, J.,Waight, A.,Hansen, S.K. (deposition date: 2003-02-06, release date: 2003-05-06, Last modification date: 2024-10-30)

Primary citation

Erlanson, D.A.,McDowell, R.S.,He, M.M.,Randal, M.,Simmons, R.L.,Kung, J.,Waight, A.,Hansen, S.K.
Discovery of a New Phosphotyrosine Mimetic for PTP1B Using Breakaway Tethering
J.Am.Chem.Soc., 125:5602-5603, 2003

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: 12733877
DOI: 10.1021/ja034440c

Experimental method

X-RAY DIFFRACTION (3.1 Å)