1bp4: Difference between revisions

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OCA

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-[[Image:1bp4.gif|left|200px]]<br /><applet load="1bp4" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1bp4, resolution 2.2&Aring;" />
-'''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.'''<br />
-==Overview==
+==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.==
-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.
+<StructureSection load='1bp4' size='340' side='right'caption='[[1bp4]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1bp4]] 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=1BP4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BP4 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALD:N-[(BENZYLOXY)CARBONYL]-L-LEUCYL-N-[(2S)-1-HYDROXY-4-METHYLPENTAN-2-YL]-L-LEUCINAMIDE'>ALD</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=1bp4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bp4 OCA], [https://pdbe.org/1bp4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bp4 RCSB], [https://www.ebi.ac.uk/pdbsum/1bp4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bp4 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/bp/1bp4_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=1bp4 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.
-==About this Structure==
+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>
-BP4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Carica_papaya Carica papaya] with ALD as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1BP4 OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9804696 9804696]
+</div>
+<div class="pdbe-citations 1bp4" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Papain|Papain]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Carica papaya]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Abdel-Mequid, S.S.]]
+[[Category: Abdel-Mequid SS]]
-[[Category: Carr, T.J.]]
+[[Category: Carr TJ]]
-[[Category: Desjarlais, R.L.]]
+[[Category: Desjarlais RL]]
-[[Category: Janson, C.A.]]
+[[Category: Janson CA]]
-[[Category: Lalonde, J.M.]]
+[[Category: Lalonde JM]]
-[[Category: Smith, W.W.]]
+[[Category: Smith WW]]
-[[Category: Thompson, S.K.]]
+[[Category: Thompson SK]]
-[[Category: Tomaszek, T.A.]]
+[[Category: Tomaszek TA]]
-[[Category: Veber, D.F.]]
+[[Category: Veber DF]]
-[[Category: Yamashita, D.S.]]
+[[Category: Yamashita DS]]
-[[Category: Zhao, B.]]
+[[Category: Zhao B]]
-[[Category: ALD]]
-[[Category: hydrolase]]
-[[Category: sulfhydryl proteinase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 11:48:30 2007''