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==Endothiapepsin in complex with Gewald reaction-derived inhibitor (6)== | ==Endothiapepsin in complex with Gewald reaction-derived inhibitor (6)== | ||
<StructureSection load='3wz7' size='340' side='right' caption='[[3wz7]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='3wz7' size='340' side='right'caption='[[3wz7]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3wz7]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3wz7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WZ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WZ7 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IXY:N-BENZYL-2-({N-[2-(1H-INDOL-3-YL)ETHYL]GLYCYL}AMINO)-4,5,6,7-TETRAHYDRO-1-BENZOTHIOPHENE-3-CARBOXAMIDE'>IXY</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IXY:N-BENZYL-2-({N-[2-(1H-INDOL-3-YL)ETHYL]GLYCYL}AMINO)-4,5,6,7-TETRAHYDRO-1-BENZOTHIOPHENE-3-CARBOXAMIDE'>IXY</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wz6|3wz6]], [[3wz8|3wz8]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3wz6|3wz6]], [[3wz8|3wz8]]</div></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Endothiapepsin Endothiapepsin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.22 3.4.23.22] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3wz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wz7 OCA], [https://pdbe.org/3wz7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wz7 RCSB], [https://www.ebi.ac.uk/pdbsum/3wz7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wz7 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
| Line 18: | Line 18: | ||
</div> | </div> | ||
<div class="pdbe-citations 3wz7" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 3wz7" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Pepsin|Pepsin]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 24: | Line 27: | ||
[[Category: Cryphonectria parasitica]] | [[Category: Cryphonectria parasitica]] | ||
[[Category: Endothiapepsin]] | [[Category: Endothiapepsin]] | ||
[[Category: Large Structures]] | |||
[[Category: Diederich, W E]] | [[Category: Diederich, W E]] | ||
[[Category: Kuhnert, M]] | [[Category: Kuhnert, M]] | ||
Revision as of 08:36, 10 August 2022
Endothiapepsin in complex with Gewald reaction-derived inhibitor (6)Endothiapepsin in complex with Gewald reaction-derived inhibitor (6)
Structural highlights
Publication Abstract from PubMedSuccessful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and beta-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation. Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors.,Kuhnert M, Koster H, Bartholomaus R, Park AY, Shahim A, Heine A, Steuber H, Klebe G, Diederich WE Angew Chem Int Ed Engl. 2015 Feb 23;54(9):2849-53. doi: 10.1002/anie.201411206., Epub 2015 Jan 28. PMID:25630461[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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