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1fq5

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[[Image:1fq5.jpg|left|200px]]<br /><applet load="1fq5" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1fq5, resolution 2.4&Aring;" />
 
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'''X-RAY STRUTURE OF A CYCLIC STATINE INHIBITOR PD-129,541 BOUND TO YEAST PROTEINASE A'''<br />
 
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==Overview==
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==X-ray structure of a cyclic statine inhibitor PD-129,541 bound to yeast proteinase A==
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Saccharopepsin is a vacuolar aspartic proteinase involved in activation of a number of hydrolases. The enzyme has great structural homology to mammalian aspartic proteinases including human renin and we have used it as a model system to study the binding of renin inhibitors by X-ray crystallography. Five medium-to-high resolution structures of saccharopepsin complexed with transition-state analogue renin inhibitors were determined. The structure of a cyclic peptide inhibitor (PD-129,541) complexed with the proteinase was solved to 2.5 A resolution. This inhibitor has low affinity for human renin yet binds very tightly to the yeast proteinase (K(i)=4 nM). The high affinity of this inhibitor can be attributed to its bulky cyclic moiety spanning P(2)-P(3)' and other residues that appear to optimally fit the binding sub-sites of the enzyme. Superposition of the saccharopepsin structure on that of renin showed that a movement of the loop 286-301 relative to renin facilitates tighter binding of this inhibitor to saccharopepsin. Our 2.8 A resolution structure of the complex with CP-108,420 shows that its benzimidazole P(3 )replacement retains one of the standard hydrogen bonds that normally involve the inhibitor's main-chain. This suggests a non-peptide lead in overcoming the problem of susceptible peptide bonds in the design of aspartic proteinase inhibitors. CP-72,647 which possesses a basic histidine residue at P(2), has a high affinity for renin (K(i)=5 nM) but proves to be a poor inhibitor for saccharopepsin (K(i)=3.7 microM). This may stem from the fact that the histidine residue would not bind favourably with the predominantly hydrophobic S(2) sub-site of saccharopepsin.
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<StructureSection load='1fq5' size='340' side='right'caption='[[1fq5]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1fq5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FQ5 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]] 2.4&#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=0GM:N-[(5S,9S,10S,13S)-9-HYDROXY-5,10-BIS(2-METHYLPROPYL)-4,7,12,16-TETRAOXO-3,6,11,17-TETRAAZABICYCLO[17.3.1]TRICOSA-1(23),19,21-TRIEN-13-YL]-3-(NAPHTHALEN-1-YL)-2-(NAPHTHALEN-1-YLMETHYL)PROPANAMIDE'>0GM</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=1fq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fq5 OCA], [https://pdbe.org/1fq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fq5 RCSB], [https://www.ebi.ac.uk/pdbsum/1fq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fq5 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CARP_YEAST CARP_YEAST] Aspartyl protease implicated in the post-translational regulation of S.cerevisiae vacuolar proteinases. Acts on YSCB, on YSCY and on itself.
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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/fq/1fq5_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=1fq5 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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1FQ5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] with <scene name='pdbligand=NDG:'>NDG</scene>, <scene name='pdbligand=NPY:'>NPY</scene>, <scene name='pdbligand=NPD:'>NPD</scene>, <scene name='pdbligand=GLU:'>GLU</scene>, <scene name='pdbligand=STA:'>STA</scene>, <scene name='pdbligand=LEU:'>LEU</scene> and <scene name='pdbligand=TRJ:'>TRJ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Saccharopepsin Saccharopepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.25 3.4.23.25] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FQ5 OCA].
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*[[Pepsin|Pepsin]]
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*[[Proteinase 3D structures|Proteinase 3D structures]]
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==Reference==
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__TOC__
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X-ray structures of five renin inhibitors bound to saccharopepsin: exploration of active-site specificity., Cronin NB, Badasso MO, J Tickle I, Dreyer T, Hoover DJ, Rosati RL, Humblet CC, Lunney EA, Cooper JB, J Mol Biol. 2000 Nov 10;303(5):745-60. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11061973 11061973]
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae]]
[[Category: Saccharomyces cerevisiae]]
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[[Category: Saccharopepsin]]
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[[Category: Badasso MO]]
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[[Category: Single protein]]
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[[Category: Cooper JB]]
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[[Category: Badasso, M O.]]
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[[Category: Cronin NB]]
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[[Category: Cooper, J B.]]
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[[Category: Dreyer T]]
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[[Category: Cronin, N B.]]
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[[Category: Hoover DJ]]
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[[Category: Dreyer, T.]]
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[[Category: Humblet CC]]
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[[Category: Hoover, D J.]]
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[[Category: Lunney EA]]
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[[Category: Humblet, C C.]]
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[[Category: Rosati RL]]
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[[Category: Lunney, E A.]]
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[[Category: Tickle IJ]]
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[[Category: Rosati, R L.]]
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[[Category: Tickle, I J.]]
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[[Category: GLU]]
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[[Category: LEU]]
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[[Category: NDG]]
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[[Category: NPD]]
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[[Category: NPY]]
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[[Category: STA]]
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[[Category: TRJ]]
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[[Category: cyclic inhibitor]]
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[[Category: ki in nanomolar range]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:41:25 2008''
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Current revision

X-ray structure of a cyclic statine inhibitor PD-129,541 bound to yeast proteinase A

PDB ID 1fq5

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