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[[Image:1apv.gif|left|200px]]


{{Structure
==CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION STATE MIMICS BOUND TO PENICILLOPEPSIN: DIFLUOROSTATINE-AND DIFLUOROSTATONE-CONTAINING PEPTIDES==
|PDB= 1apv |SIZE=350|CAPTION= <scene name='initialview01'>1apv</scene>, resolution 1.8&Aring;
<StructureSection load='1apv' size='340' side='right'caption='[[1apv]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=XYS:XYLOPYRANOSE'>XYS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>
<table><tr><td colspan='2'>[[1apv]] 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=1APV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1APV FirstGlance]. <br>
|ACTIVITY= [http://en.wikipedia.org/wiki/Penicillopepsin Penicillopepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.20 3.4.23.20]  
</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>
|GENE=  
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DFO:2,2-DIFLUORO-3-HYDROSTATINE'>DFO</scene>, <scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</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>, <scene name='pdbligand=XYS:XYLOPYRANOSE'>XYS</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=1apv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1apv OCA], [https://pdbe.org/1apv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1apv RCSB], [https://www.ebi.ac.uk/pdbsum/1apv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1apv 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/1apv_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1apv ConSurf].
<div style="clear:both"></div>


'''CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION STATE MIMICS BOUND TO PENICILLOPEPSIN: DIFLUOROSTATINE-AND DIFLUOROSTATONE-CONTAINING PEPTIDES'''
==See Also==
 
*[[Penicillopepsin|Penicillopepsin]]
 
*[[Pepsin|Pepsin]]
==Overview==
== References ==
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)
<references/>
 
__TOC__
==About this Structure==
</StructureSection>
1APV is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1APV OCA].
[[Category: Large Structures]]
 
[[Category: Penicillium janthinellum]]
==Reference==
[[Category: James MNG]]
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:[http://www.ncbi.nlm.nih.gov/pubmed/1567842 1567842]
[[Category: Sielecki AR]]
[[Category: Penicillopepsin]]
[[Category: Single protein]]
[[Category: James, M N.G.]]
[[Category: Sielecki, A R.]]
[[Category: DMF]]
[[Category: MAN]]
[[Category: SO4]]
[[Category: XYS]]
[[Category: hydrolase(acid proteinase)]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:00:47 2008''

Latest revision as of 18:27, 13 March 2024

CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION STATE MIMICS BOUND TO PENICILLOPEPSIN: DIFLUOROSTATINE-AND DIFLUOROSTATONE-CONTAINING PEPTIDESCRYSTALLOGRAPHIC ANALYSIS OF TRANSITION STATE MIMICS BOUND TO PENICILLOPEPSIN: DIFLUOROSTATINE-AND DIFLUOROSTATONE-CONTAINING PEPTIDES

Structural highlights

1apv is a 2 chain structure with sequence from Penicillium janthinellum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:, , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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'.[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Mains G, Takahashi M, Sodek J, Hofmann T. The specificity of penicillopepsin. Can J Biochem. 1971 Oct;49(10):1134-49. PMID:4946839 doi:10.1139/o71-164

1apv, resolution 1.80Å

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