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1mhw

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(New page: 200px<br /> <applet load="1mhw" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mhw, resolution 1.9&Aring;" /> '''Design of non-covale...)
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[[Image:1mhw.gif|left|200px]]<br />
 
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<applet load="1mhw" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1mhw, resolution 1.9&Aring;" />
 
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'''Design of non-covalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides'''<br />
 
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==Overview==
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==Design of non-covalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides==
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A novel series of noncovalent inhibitors of cathepsin L have been designed, to mimic the mode of autoinhibition of procathepsin L. Just like the, propeptide, these peptide-based inhibitors have a reverse-binding mode, relative to a substrate and span both the S' and S subsites of the enzyme, active site. In contrast to previous studies in which even moderate, truncation of the full-length propeptide led to rapid reduction in, potency, these blocked tripeptide-sized inhibitors maintain nanomolar, potency. Moreover, these short peptides show higher selectivity (up to, 310-fold) for inhibiting cathepsin L over K versus only 2-fold selectivity, of the 96-residue propeptide of cathepsin L. A 1.9 A X-ray, crystallographic structure of the complex of cathepsin L with one of the, inhibitors confirms the designed reverse-binding mode of the inhibitor as, well as its noncovalent nature. Enzymatic analysis also shows the, inhibitors to be resistant to hydrolysis at elevated concentrations of the, enzyme. The mode of inhibition of these molecules provides a general, strategy for inhibiting other cathepsins as well as other proteases.
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<StructureSection load='1mhw' size='340' side='right'caption='[[1mhw]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1mhw]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MHW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MHW FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BP4:BIPHENYL-4-YLACETIC+ACID'>BP4</scene>, <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene>, <scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=PEA:2-PHENYLETHYLAMINE'>PEA</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1mhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mhw OCA], [https://pdbe.org/1mhw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1mhw RCSB], [https://www.ebi.ac.uk/pdbsum/1mhw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1mhw ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CATL1_HUMAN CATL1_HUMAN] Important for the overall degradation of proteins in lysosomes.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mh/1mhw_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1mhw ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1MHW is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Cathepsin_L Cathepsin L], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.15 3.4.22.15] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1MHW OCA].
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*[[Cathepsin 3D structures|Cathepsin 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Design of noncovalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides., Chowdhury SF, Sivaraman J, Wang J, Devanathan G, Lachance P, Qi H, Menard R, Lefebvre J, Konishi Y, Cygler M, Sulea T, Purisima EO, J Med Chem. 2002 Nov 21;45(24):5321-9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12431059 12431059]
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[[Category: Cathepsin L]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Chowdhury, S.]]
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[[Category: Chowdhury S]]
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[[Category: Cygler, M.]]
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[[Category: Cygler M]]
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[[Category: Devanathan, G.]]
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[[Category: Devanathan G]]
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[[Category: Konishi, Y.]]
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[[Category: Konishi Y]]
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[[Category: Lachance, P.]]
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[[Category: Lachance P]]
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[[Category: Lefebvre, J.]]
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[[Category: Lefebvre J]]
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[[Category: Menard, R.]]
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[[Category: Menard R]]
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[[Category: Purisima, E.O.]]
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[[Category: Purisima EO]]
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[[Category: Qi, H.]]
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[[Category: Qi H]]
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[[Category: Sivaraman, J.]]
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[[Category: Sivaraman J]]
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[[Category: Sulea, T.]]
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[[Category: Sulea T]]
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[[Category: Wang, J.]]
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[[Category: Wang J]]
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[[Category: cathepsin l]]
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[[Category: cysteine protease]]
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[[Category: inhibitor complex]]
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[[Category: x-ray structure]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:11:36 2007''
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Current revision

Design of non-covalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides

PDB ID 1mhw

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