5eg4: Difference between revisions
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The | ==BOVINE TRYPSIN IN COMPLEX WITH CYCLIC INHIBITOR== | ||
<StructureSection load='5eg4' size='340' side='right' caption='[[5eg4]], [[Resolution|resolution]] 1.32Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5eg4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EG4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EG4 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5N7:(13S,16R)-N-(4-CARBAMIMIDOYLBENZYL)-16-((N-CYCLOHEXYLSULFAMOYL)AMINO)-3,9,15-TRIOXO-2,10,14-TRIAZA-6(1,4)-PIPERAZINA-1,11(1,4)-DIBENZENACYCLOHEPTADECAPHANE-13-CARBOXAMIDE'>5N7</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mtb|4mtb]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] </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=5eg4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eg4 OCA], [http://pdbe.org/5eg4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eg4 RCSB], [http://www.ebi.ac.uk/pdbsum/5eg4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5eg4 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin. | |||
Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.,Hinkes S, Wuttke A, Saupe SM, Ivanova T, Wagner S, Knorlein A, Heine A, Klebe G, Steinmetzer T J Med Chem. 2016 Jun 17. PMID:27280436<ref>PMID:27280436</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5eg4" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Trypsin]] | |||
[[Category: Heine, A]] | |||
[[Category: Klebe, G]] | [[Category: Klebe, G]] | ||
[[Category: Knoerlein, A]] | [[Category: Knoerlein, A]] | ||
[[Category: Steinmetzer, T]] | |||
[[Category: Wagner, S]] | [[Category: Wagner, S]] | ||
[[Category: Digestion]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Metal-binding]] | |||
Revision as of 14:44, 14 July 2016
BOVINE TRYPSIN IN COMPLEX WITH CYCLIC INHIBITORBOVINE TRYPSIN IN COMPLEX WITH CYCLIC INHIBITOR
Structural highlights
Publication Abstract from PubMedNew macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin. Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.,Hinkes S, Wuttke A, Saupe SM, Ivanova T, Wagner S, Knorlein A, Heine A, Klebe G, Steinmetzer T J Med Chem. 2016 Jun 17. PMID:27280436[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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