View source for 1apw


==CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION STATE MIMICS BOUND TO PENICILLOPEPSIN: DIFLUOROSTATINE-AND DIFLUOROSTATONE-CONTAINING PEPTIDES==
<StructureSection load='1apw' size='340' side='right'caption='[[1apw]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1apw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Penicillium_janthinellum Penicillium janthinellum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1APW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1APW 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DFI:2,2-DIFLUOROSTATINE'>DFI</scene>, <scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=HSY:ALPHA-L-XYLOPYRANOSE'>HSY</scene>, <scene name='pdbligand=IVA:ISOVALERIC+ACID'>IVA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1apw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1apw OCA], [https://pdbe.org/1apw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1apw RCSB], [https://www.ebi.ac.uk/pdbsum/1apw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1apw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PEPA1_PENJA PEPA1_PENJA] Secreted aspartic endopeptidase that allows assimilation of proteinaceous substrates. The scissile peptide bond is attacked by a nucleophilic water molecule activated by two aspartic residues in the active site. Shows a broad primary substrate specificity. Favors hydrophobic residues at the P1 and P1' positions, but can also activate trypsinogen and hydrolyze the B chain of insulin between positions 'Gly-20' and 'Glu-21'.<ref>PMID:4946839</ref> 
== 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/ap/1apw_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=1apw ConSurf].
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== Publication Abstract from PubMed ==
Difluorostatine- and difluorostatone-containing peptides have been evaluated as potent inhibitors of penicillopepsin, a member of the aspartic proteinase family of enzymes. Isovaleryl-Val-Val-StaF2NHCH3 [StaF2 = (S)-4-amino-2,2-difluoro-(R)-3-hydroxy-6-methylheptanoic acid] and isovaleryl-Val-Val-StoF2NHCH3 [StoF2 = (S)-4-amino-2,2-difluoro-3-oxo-6-methylheptanoic acid] have measured Ki's of 10 x 10(-9) and 1 x 10(-9) M, respectively, with this fungal proteinase. The StoF2-containing peptide binds 32-fold more tightly to the enzyme than the analogous peptide containing the non-fluorinated statine ethyl ester. Each compound was cocrystallized with penicillopepsin, intensity data were collected to 1.8-A resolution, and the atomic coordinates were refined to an R factor [formula: see text] of 0.131 for both complexes. The inhibitors bind in the active site of penicillopepsin in much the same fashion as do other statine-containing inhibitors of penicillopepsin analyzed earlier [James, M. N. G., Sielecki, A. Salituro, F., Rich, D. H., &amp; Hofmann, T. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 6137-6141; James, M.N.G., Sielecki, A., &amp; Hofmann, T. (1985) in Aspartic Proteinases and their Inhibitors (Kosta, V., Ed.) pp 163-177, Walter deGruyter, Berlin]. The (R)-3-hydroxyl group in StaF2 binds between the active site carboxyl groups of Asp33 and Asp213, making hydrogen-bonding contacts to each one. The ketone functional group of the StoF2 inhibitor is bound as a hydrated species, with the gem-diol situated between the two aspartic acid carboxyl groups in a manner similar to that predicted for the tetrahedral intermediate expected during the catalytic hydrolysis of a peptide bond [James, M. N. G., &amp; Sielecki, A. (1985) Biochemistry 24, 3701-3713]. One hydrogen-bonding interaction from the "outer" hydroxyl group is made to O delta 1 of Asp33, and the "inner" hydroxyl group forms two hydrogen-bonding contacts, one to each of the carboxyl groups of Asp33 (O delta 2) and Asp213 (O delta 2). The only structural difference between the StaF2 and StoF2 inhibitors that accounts for the factor of 10 in their Ki's is the additional (R)-3-OH group on the tetrahedral sp3 carbon atom of the hydrated StoF2 inhibitor. The intermolecular interactions involving the fluorine atoms of each inhibitor are normal van der Waals contacts to one of the carboxyl oxygen atoms of Asp213 (F2-O delta 2 Asp213, 2.9 A). The observed stereochemistry of the bound StoF2 group in the active site of penicillopepsin has stimulated our reappraisal of the catalytic pathway for the aspartic proteinases.(ABSTRACT TRUNCATED AT 400 WORDS)

Crystallographic analysis of transition state mimics bound to penicillopepsin: difluorostatine- and difluorostatone-containing peptides.,James MN, Sielecki AR, Hayakawa K, Gelb MH Biochemistry. 1992 Apr 21;31(15):3872-86. PMID:1567842<ref>PMID:1567842</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Penicillopepsin|Penicillopepsin]]
*[[Pepsin|Pepsin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Penicillium janthinellum]]
[[Category: James MNG]]
[[Category: Sielecki AR]]