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PDBsum entry 4bcd
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PDB id:
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Hydrolase
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Title:
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Prolyl oligopeptidase from porcine brain with a non-covalently bound p2-substituted n-acyl-prolylpyrrolidine inhibitor
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Structure:
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Prolyl endopeptidase. Chain: a. Synonym: pe, post-proline cleaving enzyme. Engineered: yes
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Source:
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Sus scrofa. Pig. Organism_taxid: 9823. Organ: brain. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.50Å
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R-factor:
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0.159
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R-free:
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0.186
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Authors:
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P.Vanderveken,V.Fulop,D.Rea,M.Gerard,R.Vanelzen,J.Joossens,J.D.Cheng, V.Baekelandt,I.Demeester,A.M.Lambeir,K.Augustyns
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Key ref:
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P.Van der Veken
et al.
(2012).
P2-substituted N-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase: biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy.
J Med Chem,
55,
9856-9867.
PubMed id:
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Date:
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01-Oct-12
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Release date:
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13-Mar-13
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PROCHECK
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Headers
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References
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P23687
(PPCE_PIG) -
Prolyl endopeptidase from Sus scrofa
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Seq:
Struc:
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710 a.a.
710 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.3.4.21.26
- prolyl oligopeptidase.
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Reaction:
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Hydrolysis of Pro-|-Xaa >> Ala-|-Xaa in oligopeptides.
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J Med Chem
55:9856-9867
(2012)
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PubMed id:
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P2-substituted N-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase: biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy.
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P.Van der Veken,
V.Fülöp,
D.Rea,
M.Gerard,
R.Van Elzen,
J.Joossens,
J.D.Cheng,
V.Baekelandt,
I.De Meester,
A.M.Lambeir,
K.Augustyns.
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ABSTRACT
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We have investigated the effect of regiospecifically introducing substituents in
the P2 part of the typical dipeptide derived basic structure of PREP inhibitors.
This hitherto unexplored modification type can be used to improve target
affinity, selectivity, and physicochemical parameters in drug discovery programs
focusing on PREP inhibitors. Biochemical evaluation of the produced inhibitors
identified several substituent types that significantly increase target
affinity, thereby reducing the need for an electrophilic "warhead"
functionality. Pronounced PREP specificity within the group of Clan SC proteases
was generally observed. Omission of the P1 electrophilic function did not affect
the overall binding mode of three representative compounds, as studied by X-ray
crystallography, while the P2 substituents were demonstrated to be accommodated
in a cavity of PREP that, to date, has not been probed by inhibitors. Finally,
we report on results of selected inhibitors in a SH-SY5Y cellular model of
synucleinopathy and demonstrate a significant antiaggregation effect on
α-synuclein.
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Links
