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PDBsum entry 1lqf
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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 structure of ptp-1b in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates.
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Authors
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E.Asante-Appiah,
S.Patel,
C.Dufresne,
P.Roy,
Q.Wang,
V.Patel,
R.W.Friesen,
C.Ramachandran,
J.W.Becker,
Y.Leblanc,
B.P.Kennedy,
G.Scapin.
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Ref.
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Biochemistry, 2002,
41,
9043-9051.
[DOI no: ]
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PubMed id
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Abstract
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Inhibitors of PTP-1B could be therapeutically beneficial in the treatment of
type 2 diabetes. Owing to the large number of phosphatases in the cell,
inhibitors against PTP-1B must not only be potent but selective as well.
N-Benzoyl-L-glutamyl-[4-phosphono(difluoromethyl)]-L-phenylalanine-[4-phosphono(difluoro-methyl)]-L-phenylalanineamide
(BzN-EJJ-amide) is a low nanomolar inhibitor of PTP-1B that shows selectivity
over several protein tyrosine phosphatases. To gain an insight into the basis of
its potency and selectivity, we evaluated several analogues of the inhibitor and
introduced amino acid substitutions into PTP-1B by site-directed mutagenesis. We
also determined the crystal structure of PTP-1B in complex with BzN-EJJ-amide at
2.5 A resolution. Our results indicate that the high inhibitory potency is due
to interactions of several of its chemical groups with specific protein
residues. An interaction between BzN-EJJ-amide and Asp48 is of particular
significance, as substitution of Asp48 to alanine resulted in a 100-fold loss in
potency. The crystal structure also revealed an unexpected binding orientation
for a bisphosphonate inhibitor on PTP-1B, where the second
difluorophosphonomethyl phenylalanine (F(2)PMP) moiety is bound close to Arg47
rather than in the previously identified second aryl phosphate site demarked by
Arg24 and Arg254. Our results suggest that potent and selective PTP-1B
inhibitors may be designed by targeting the region containing Arg47 and Asp48.
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Secondary reference #1
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Title
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The yrd motif is a major determinant of substrate and inhibitor specificity in t-Cell protein-Tyrosine phosphatase.
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Authors
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E.Asante-Appiah,
K.Ball,
K.Bateman,
K.Skorey,
R.Friesen,
C.Desponts,
P.Payette,
C.Bayly,
R.Zamboni,
G.Scapin,
C.Ramachandran,
B.P.Kennedy.
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Ref.
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J Biol Chem, 2001,
276,
26036-26043.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. A multiple alignment of protein-tyrosine
phosphatases amino acid sequences showing the region spanning
the YXB motif (underlined and in bold). The extent of
relatedness was computed relative to PTP1B by analyzing the
catalytic domains (residues 1-240 in PTP1B) of the PTPs. The
percent identity with respect to PTP1B is shown on the right
side of the figure. The single letter code for amino acids has
been used. The multiple sequence alignments was performed with
the aide of ClustalW (25). The accession code for the PTPs in
the Swiss-prot data base is as follows (top to bottom):
ptn1_human, ptn2_human, ptnb_human, ptn6_human, ptnF_human,
ptn9_human, ptnM_human, ptnD_human, ptnB_human, ptnE_human,
ptnA_human, ptn4_human, ptnG_human, ptn7_human, CD45_human,
ptn3_human, ptnC_human, ptnF_human, ptnJ_human.
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Figure 6.
Fig. 6. Subsite amino acid preferences for wild-type
TCPTP (black) and R49K derivative (white). The peptide library,
DADX[4]pYL, where X[4] represents the individual presence of all
19 naturally occurring amino acids (except cysteine) was used in
an affinity selection protocol (see "Methods").
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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