1nwl
From Proteopedia
Crystal structure of the PTP1B complexed with SP7343-SP7964, a pTyr mimetic
Contents |
Overview
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.
Disease
Known disease associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this Structure
1NWL is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Discovery of a new phosphotyrosine mimetic for PTP1B using breakaway tethering., Erlanson DA, McDowell RS, He MM, Randal M, Simmons RL, Kung J, Waight A, Hansen SK, J Am Chem Soc. 2003 May 14;125(19):5602-3. PMID:12733877 Page seeded by OCA on Sat May 3 03:03:58 2008
