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PDBsum entry 1pxh
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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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Crystal structure of ptp1b complexed with a potent and selective bidentate inhibitor.
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Authors
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J.P.Sun,
A.A.Fedorov,
S.Y.Lee,
X.L.Guo,
K.Shen,
D.S.Lawrence,
S.C.Almo,
Z.Y.Zhang.
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Ref.
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J Biol Chem, 2003,
278,
12406-12414.
[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 as an important
regulator in several signaling pathways including those initiated by insulin and
leptin. Potent and specific PTP1B inhibitors could serve as useful tools in
elucidating the physiological functions of PTP1B and may constitute valuable
therapeutics in the treatment of several human diseases. We have determined the
crystal structure of PTP1B in complex with compound 2, the most potent and
selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution
reveals that compound 2 simultaneously binds to the active site and a unique
proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural
data are further corroborated by results from kinetic analyses of the
interactions of PTP1B and its site-directed mutants with compound 2 and several
of its variants. Although many of the residues important for interactions
between PTP1B and compound 2 are not unique to PTP1B, the combinations of all
contact residues differ between PTP isozymes, which provide a structural basis
for potent and selective PTP1B inhibition. Our data further suggest that potent,
yet highly selective, PTP1B inhibitory agents can be acquired by targeting the
area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the
previously identified second aryl phosphate-binding pocket.
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Figure 4.
Fig. 4. Interactions between 2 and PTP1B. a, H-bonding
(blue dotted lines) and polar interactions (red dotted lines);
b, hydrophobic interactions (orange dotted lines), and; c,
interactions between the two fluorine atoms in F[2]Pmp and
PTP1B. The cut-off distance used is 3.2 Å for hydrogen
bonds, 4.0 Å for electrostatic or polar interactions, and
4.5 Å for hydrophobic interactions.
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Figure 5.
Fig. 5. Interactions of Arg-47 and Lys-41 with the EGFR
peptide (a), the PTP1B consensus peptide (b), compound 2 (c),
and compound 4 (d). Hydrophobic interactions are indicated by
orange dotted lines, H-bonds by blue dotted lines, and polar
interactions by red dotted lines.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
12406-12414)
copyright 2003.
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