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PDBsum entry 2a8b
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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 structures and inhibitor identification for ptpn5, Ptprr and ptpn7: a family of human mapk-Specific protein tyrosine phosphatases.
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Authors
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J.Eswaran,
J.P.Von kries,
B.Marsden,
E.Longman,
J.E.Debreczeni,
E.Ugochukwu,
A.Turnbull,
W.H.Lee,
S.Knapp,
A.J.Barr.
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Ref.
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Biochem J, 2006,
395,
483-491.
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PubMed id
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Abstract
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Protein tyrosine phosphatases PTPN5, PTPRR and PTPN7 comprise a family of
phosphatases that specifically inactivate MAPKs (mitogen-activated protein
kinases). We have determined high-resolution structures of all of the human
family members, screened them against a library of 24000 compounds and
identified two classes of inhibitors, cyclopenta[c]quinolinecarboxylic acids and
2,5-dimethylpyrrolyl benzoic acids. Comparative structural analysis revealed
significant differences within this conserved family that could be explored for
the design of selective inhibitors. PTPN5 crystallized, in two distinct crystal
forms, with a sulphate ion in close proximity to the active site and the WPD
(Trp-Pro-Asp) loop in a unique conformation, not seen in other PTPs, ending in a
3(10)-helix. In the PTPN7 structure, the WPD loop was in the closed conformation
and part of the KIM (kinase-interaction motif) was visible, which forms an
N-terminal aliphatic helix with the phosphorylation site Thr66 in an accessible
position. The WPD loop of PTPRR was open; however, in contrast with the
structure of its mouse homologue, PTPSL, a salt bridge between the conserved
lysine and aspartate residues, which has been postulated to confer a more rigid
loop structure, thereby modulating activity in PTPSL, does not form in PTPRR.
One of the identified inhibitor scaffolds, cyclopenta[c]quinoline, was docked
successfully into PTPRR, suggesting several possibilities for hit expansion. The
determined structures together with the established SAR (structure-activity
relationship) propose new avenues for the development of selective inhibitors
that may have therapeutic potential for treating neurodegenerative diseases in
the case of PTPRR or acute myeloblastic leukaemia targeting PTPN7.
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