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==PROLYL OLIGOPEPTIDASE FROM PORCINE BRAIN WITH A COVALENTLY BOUND P2- substituted N-acyl-prolylpyrrolidine inhibitor== | |||
<StructureSection load='4bcb' size='340' side='right' caption='[[4bcb]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4bcb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BCB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BCB FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4I4:(5R,6R,8S)-8-(3-{[AMINO(IMINO)METHYL]AMINO}PHENYL)-5-CYCLOHEXYL-6-HYDROXY-3-OXO-1-PHENYL-2,7-DIOXA-4-AZA-6-PHOSPHANONAN-9-OIC+ACID+6-OXIDE'>4I4</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TAM:TRIS(HYDROXYETHYL)AMINOMETHANE'>TAM</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1e5t|1e5t]], [[1e8m|1e8m]], [[1e8n|1e8n]], [[1h2w|1h2w]], [[1h2x|1h2x]], [[1h2y|1h2y]], [[1h2z|1h2z]], [[1o6f|1o6f]], [[1o6g|1o6g]], [[1qfm|1qfm]], [[1qfs|1qfs]], [[1uoo|1uoo]], [[1uop|1uop]], [[1uoq|1uoq]], [[1vz2|1vz2]], [[1vz3|1vz3]], [[2xdw|2xdw]], [[4amy|4amy]], [[4amz|4amz]], [[4an0|4an0]], [[4an1|4an1]], [[4ax4|4ax4]], [[4bcc|4bcc]], [[4bcd|4bcd]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Prolyl_oligopeptidase Prolyl oligopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.26 3.4.21.26] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bcb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bcb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bcb RCSB], [http://www.ebi.ac.uk/pdbsum/4bcb PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 alpha-synuclein. | |||
P2-substituted N-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase: biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy.,Van der Veken P, Fulop V, Rea D, Gerard M, Van Elzen R, Joossens J, Cheng JD, Baekelandt V, De Meester I, Lambeir AM, Augustyns K J Med Chem. 2012 Nov 26;55(22):9856-67. doi: 10.1021/jm301060g. Epub 2012 Nov 13. PMID:23121075<ref>PMID:23121075</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[Prolyl Endopeptidase|Prolyl Endopeptidase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Prolyl oligopeptidase]] | [[Category: Prolyl oligopeptidase]] | ||
[[Category: Sus scrofa]] | [[Category: Sus scrofa]] | ||
[[Category: Augustyns, K | [[Category: Augustyns, K]] | ||
[[Category: Baekelandt, V | [[Category: Baekelandt, V]] | ||
[[Category: Cheng, J D | [[Category: Cheng, J D]] | ||
[[Category: DeMeester, I | [[Category: DeMeester, I]] | ||
[[Category: Fulop, V | [[Category: Fulop, V]] | ||
[[Category: Gerard, M | [[Category: Gerard, M]] | ||
[[Category: Joossens, J | [[Category: Joossens, J]] | ||
[[Category: Lambeir, A M | [[Category: Lambeir, A M]] | ||
[[Category: Rea, D | [[Category: Rea, D]] | ||
[[Category: VanDerVeken, P | [[Category: VanDerVeken, P]] | ||
[[Category: VanElzen, R | [[Category: VanElzen, R]] | ||
[[Category: Alpha-beta-hydrolase]] | [[Category: Alpha-beta-hydrolase]] | ||
[[Category: Alzheimers disease]] | [[Category: Alzheimers disease]] | ||