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PDBsum entry 1q6s
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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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The structural basis for the selectivity of benzotriazole inhibitors of ptp1b.
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Authors
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G.Scapin,
S.B.Patel,
J.W.Becker,
Q.Wang,
C.Desponts,
D.Waddleton,
K.Skorey,
W.Cromlish,
C.Bayly,
M.Therien,
J.Y.Gauthier,
C.S.Li,
C.K.Lau,
C.Ramachandran,
B.P.Kennedy,
E.Asante-Appiah.
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Ref.
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Biochemistry, 2003,
42,
11451-11459.
[DOI no: ]
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PubMed id
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Abstract
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Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of
the insulin signaling pathway and represents an attractive target for the design
of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the
structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by
targeting a secondary aryl phosphate-binding site as well as the catalytic site.
We report here the crystal structures of PTP1B in complex with first and second
generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds
bind in a previously unexploited binding pocket near the primary binding site,
the second generation compounds also reach into the secondary binding site, and
exhibit moderate selectivity for PTP1B over the closely related T-cell
phosphatase. The molecular basis for the selectivity has been confirmed by
single point mutation at position 52, where the two phosphatases differ by a
phenylalanine-to-tyrosine switch. These compounds present a novel platform for
the development of potent and selective PTP1B inhibitors.
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