1bqi: Difference between revisions
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< | ==USE OF PAPAIN AS A MODEL FOR THE STRUCTURE-BASED DESIGN OF CATHEPSIN K INHIBITORS. CRYSTAL STRUCTURES OF TWO PAPAIN INHIBITOR COMPLEXES DEMONSTRATE BINDING TO S'-SUBSITES.== | ||
<StructureSection load='1bqi' size='340' side='right'caption='[[1bqi]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1bqi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Carica_papaya Carica papaya]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BQI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BQI FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SBA:CARBOBENZYLOXY-(L)-LEUCINYL-(L)LEUCINYL+METHOXYMETHYLKETONE'>SBA</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1bqi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bqi OCA], [https://pdbe.org/1bqi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bqi RCSB], [https://www.ebi.ac.uk/pdbsum/1bqi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bqi ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PAPA1_CARPA PAPA1_CARPA] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bq/1bqi_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1bqi ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Papain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes. | |||
Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.,LaLonde JM, Zhao B, Smith WW, Janson CA, DesJarlais RL, Tomaszek TA, Carr TJ, Thompson SK, Oh HJ, Yamashita DS, Veber DF, Abdel-Meguid SS J Med Chem. 1998 Nov 5;41(23):4567-76. PMID:9804696<ref>PMID:9804696</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1bqi" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Papain|Papain]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
== | |||
< | |||
[[Category: Carica papaya]] | [[Category: Carica papaya]] | ||
[[Category: Abdel-Mequid | [[Category: Large Structures]] | ||
[[Category: Carr | [[Category: Abdel-Mequid SS]] | ||
[[Category: Desjarlais | [[Category: Carr TJ]] | ||
[[Category: Janson | [[Category: Desjarlais RL]] | ||
[[Category: Lalonde | [[Category: Janson CA]] | ||
[[Category: Smith | [[Category: Lalonde JM]] | ||
[[Category: Thompson | [[Category: Smith WW]] | ||
[[Category: Tomaszek | [[Category: Thompson SK]] | ||
[[Category: Veber | [[Category: Tomaszek TA]] | ||
[[Category: Yamashita | [[Category: Veber DF]] | ||
[[Category: Zhao | [[Category: Yamashita DS]] | ||
[[Category: Zhao B]] | |||
Latest revision as of 09:26, 30 October 2024
USE OF PAPAIN AS A MODEL FOR THE STRUCTURE-BASED DESIGN OF CATHEPSIN K INHIBITORS. CRYSTAL STRUCTURES OF TWO PAPAIN INHIBITOR COMPLEXES DEMONSTRATE BINDING TO S'-SUBSITES.USE OF PAPAIN AS A MODEL FOR THE STRUCTURE-BASED DESIGN OF CATHEPSIN K INHIBITORS. CRYSTAL STRUCTURES OF TWO PAPAIN INHIBITOR COMPLEXES DEMONSTRATE BINDING TO S'-SUBSITES.
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPapain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes. Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.,LaLonde JM, Zhao B, Smith WW, Janson CA, DesJarlais RL, Tomaszek TA, Carr TJ, Thompson SK, Oh HJ, Yamashita DS, Veber DF, Abdel-Meguid SS J Med Chem. 1998 Nov 5;41(23):4567-76. PMID:9804696[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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