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PDBsum entry 1nwe
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Discovery of a new phosphotyrosine mimetic for ptp1b using breakaway tethering.
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Authors
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D.A.Erlanson,
R.S.Mcdowell,
M.M.He,
M.Randal,
R.L.Simmons,
J.Kung,
A.Waight,
S.K.Hansen.
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Ref.
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J Am Chem Soc, 2003,
125,
5602-5603.
[DOI no: ]
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PubMed id
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Abstract
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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.
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