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PDBsum entry 1lqf
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Structure of ptp1b in complex with a peptidic bisphosphonate inhibitor
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Structure:
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Protein-tyrosine phosphatase, non-receptor type 1. Chain: a, b, c, d. Fragment: catalytic domain (residues 1-283). Synonym: ptp1b, protein tyrosine phosphatase 1b. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.50Å
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R-factor:
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0.228
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R-free:
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0.286
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Authors:
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E.Asante-Appiah,S.Patel,C.Dufresne,G.Scapin
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Key ref:
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E.Asante-Appiah
et al.
(2002).
The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates.
Biochemistry,
41,
9043-9051.
PubMed id:
DOI:
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Date:
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10-May-02
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Release date:
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24-Jul-02
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PROCHECK
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Headers
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References
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P18031
(PTN1_HUMAN) -
Tyrosine-protein phosphatase non-receptor type 1 from Homo sapiens
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Seq:
Struc:
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435 a.a.
287 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.1.3.48
- protein-tyrosine-phosphatase.
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Reaction:
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O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate
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O-phospho-L-tyrosyl-[protein]
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+
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H2O
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=
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L-tyrosyl-[protein]
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+
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phosphate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Biochemistry
41:9043-9051
(2002)
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PubMed id:
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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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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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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.Xie,
and
C.T.Seto
(2007).
A two stage click-based library of protein tyrosine phosphatase inhibitors.
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Bioorg Med Chem,
15,
458-473.
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E.Asante-Appiah,
S.Patel,
C.Desponts,
J.M.Taylor,
C.Lau,
C.Dufresne,
M.Therien,
R.Friesen,
J.W.Becker,
Y.Leblanc,
B.P.Kennedy,
and
G.Scapin
(2006).
Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
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J Biol Chem,
281,
8010-8015.
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PDB codes:
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P.J.Ala,
L.Gonneville,
M.C.Hillman,
M.Becker-Pasha,
M.Wei,
B.G.Reid,
R.Klabe,
E.W.Yue,
B.Wayland,
B.Douty,
P.Polam,
Z.Wasserman,
M.Bower,
A.P.Combs,
T.C.Burn,
G.F.Hollis,
and
R.Wynn
(2006).
Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
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J Biol Chem,
281,
32784-32795.
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PDB codes:
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L.Bialy,
and
H.Waldmann
(2005).
Inhibitors of protein tyrosine phosphatases: next-generation drugs?
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Angew Chem Int Ed Engl,
44,
3814-3839.
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S.D.Taylor,
and
B.Hill
(2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
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Expert Opin Investig Drugs,
13,
199-214.
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Y.Romsicki,
M.Reece,
J.Y.Gauthier,
E.Asante-Appiah,
and
B.P.Kennedy
(2004).
Protein tyrosine phosphatase-1B dephosphorylation of the insulin receptor occurs in a perinuclear endosome compartment in human embryonic kidney 293 cells.
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J Biol Chem,
279,
12868-12875.
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J.P.Sun,
A.A.Fedorov,
S.Y.Lee,
X.L.Guo,
K.Shen,
D.S.Lawrence,
S.C.Almo,
and
Z.Y.Zhang
(2003).
Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor.
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J Biol Chem,
278,
12406-12414.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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