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==PROLYL OLIGOPEPTIDASE FROM PORCINE BRAIN WITH A COVALENTLY BOUND INHIBITOR IC-4== | |||
<StructureSection load='4an1' size='340' side='right' caption='[[4an1]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4an1]] 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=4AN1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AN1 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2P8:(2S)-N-BENZYL-2-({(2S)-2-[(1R)-1,2-DIHYDROXYETHYL]PYRROLIDIN-1-YL}CARBONYL)PYRROLIDINE-1-CARBOXAMIDE'>2P8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]]</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=4an1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4an1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4an1 RCSB], [http://www.ebi.ac.uk/pdbsum/4an1 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Altered prolyl oligopeptidase (PREP) activity is found in many common neurological and other genetic disorders, and in some cases PREP inhibition may be a promising treatment. The active site of PREP resides in an internal cavity; in addition to the direct interaction between active site and substrate or inhibitor, the pathway to reach the active site (the gating mechanism) must be understood for more rational inhibitor design and understanding PREP function. The gating mechanism of PREP has been investigated through molecular dynamics (MD) simulation combined with crystallographic and mutagenesis studies. The MD results indicate the inter-domain loop structure, comprised of 3 loops at residues, 189-209 (loop A), 577-608 (loop B), and 636-646 (loop C) (porcine PREP numbering), are important components of the gating mechanism. The results from enzyme kinetics of PREP variants also support this hypothesis: When loop A is (1) locked to loop B through a disulphide bridge, all enzyme activity is halted, (2) nicked, enzyme activity is increased, and (3) removed, enzyme activity is only reduced. Limited proteolysis study also supports the hypothesis of a loop A driven gating mechanism. The MD results show a stable network of H-bonds that hold the two protein domains together. Crystallographic study indicates that a set of known PREP inhibitors inhabit a common binding conformation, and this H-bond network is not significantly altered. Thus the domain separation, seen to occur in lower taxa, is not involved in the gating mechanism for mammalian PREP. In two of the MD simulations we observed a conformational change that involved the breaking of the H-bond network holding loops A and B together. We also found that this network was more stable when the active site was occupied, thus decreasing the likelihood of this transition. | |||
Molecular dynamics, crystallography and mutagenesis studies on the substrate gating mechanism of prolyl oligopeptidase.,Kaszuba K, Rog T, Danne R, Canning P, Fulop V, Juhasz T, Szeltner Z, St Pierre JF, Garcia-Horsman A, Mannisto PT, Karttunen M, Hokkanen J, Bunker A Biochimie. 2012 Jun;94(6):1398-411. Epub 2012 Mar 30. PMID:22484394<ref>PMID:22484394</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Prolyl Endopeptidase|Prolyl Endopeptidase]] | *[[Prolyl Endopeptidase|Prolyl Endopeptidase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Prolyl oligopeptidase]] | [[Category: Prolyl oligopeptidase]] | ||
[[Category: Sus scrofa]] | [[Category: Sus scrofa]] | ||
[[Category: Bunker, A | [[Category: Bunker, A]] | ||
[[Category: Canning, P | [[Category: Canning, P]] | ||
[[Category: Danne, R | [[Category: Danne, R]] | ||
[[Category: Fulop, V | [[Category: Fulop, V]] | ||
[[Category: Garcia-Horsman, A | [[Category: Garcia-Horsman, A]] | ||
[[Category: Hokkanen, J | [[Category: Hokkanen, J]] | ||
[[Category: Juhasz, T | [[Category: Juhasz, T]] | ||
[[Category: Karttunen, M | [[Category: Karttunen, M]] | ||
[[Category: Kaszuba, K | [[Category: Kaszuba, K]] | ||
[[Category: Mannisto, P T | [[Category: Mannisto, P T]] | ||
[[Category: Pierre, J F.St- | [[Category: Pierre, J F.St-]] | ||
[[Category: Rog, T | [[Category: Rog, T]] | ||
[[Category: Szeltner, Z | [[Category: Szeltner, Z]] | ||
[[Category: Alpha/beta-hydrolase]] | [[Category: Alpha/beta-hydrolase]] | ||
[[Category: Amnesia]] | [[Category: Amnesia]] | ||
[[Category: Beta-propeller]] | [[Category: Beta-propeller]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||