1ppl

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(New page: 200px<br /><applet load="1ppl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ppl, resolution 1.7&Aring;" /> '''CRYSTALLOGRAPHIC ANAL...)
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[[Image:1ppl.jpg|left|200px]]<br /><applet load="1ppl" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1ppl, resolution 1.7&Aring;" />
 
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'''CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN: PHOSPHORUS-CONTAINING PEPTIDE ANALOGUES'''<br />
 
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==Overview==
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==CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN: PHOSPHORUS-CONTAINING PEPTIDE ANALOGUES==
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The molecular structures of three phosphorus-based peptide inhibitors of, aspartyl proteinases complexed with penicillopepsin [1, Iva-L-Val-L-Val-StaPOEt [Iva = isovaleryl, StaP = the phosphinic acid, analogue of statine [(S)-4-amino-(S)-3-hydroxy-6-methylheptanoic acid], (IvaVVStaPOEt)]; 2, Iva-L-Val-L-Val-L-LeuP-(O)Phe-OMe [LeuP = the, phosphinic acid analogue of L-leucine; (O)Phe = L-3-phenyllactic acid; OMe, = methyl ester] [Iva VVLP(O)FOMe]; and 3, Cbz-L-Ala-L-Ala-L-LeuP-(O)-Phe-OMe (Cbz = benzyloxycarbonyl), [CbzAALP(O)FOMe]] have been determined by X-ray crystallography and, refined to crystallographic agreement factors, R ( = sigma parallel to F0, magnitude of - Fc parallel to/sigma magnitude of F0), of 0.132, 0.131, and, 0.134, respectively. These inhibitors were designed to be structural, mimics of the tetrahederal transition-state intermediate encountered, during aspartic proteinase catalysis. They are potent inhibitors of, penicillopepsin with Ki values of 1, 22 nM; 2, 2.8 nM; and 3, 1600 nM, respectively [Bartlett, P. A., Hanson, J. E., &amp; Giannousis, P. P. (1990), J. Org. Chem. 55, 6268-6274]. All three of these phosphorus-based, inhibitors bind virtually identically in the active site of, penicillopepsin in a manner that closely approximates that expected for, the transition state [James, M. N. G., Sielecki, A.R., Hayakawa, K., &amp;, Gelb, M. H. (1992) Biochemistry 31, 3872-3886]. The pro-S oxygen atom of, the two phosphonate inhibitors and of the phosphinate group of the StaP, inhibitor make very short contact distances (approximately 2.4 A) to the, carboxyl oxygen atom, O delta 1, of Asp33 on penicillopepsin. We have, interpreted this distance and the stereochemical environment of the, carboxyl and phosphonate groups in terms of a hydrogen bond that most, probably has a symmetric single-well potential energy function. The pro-R, oxygen atom is the recipient of a hydrogen bond from the carboxyl group of, Asp213. Thus, we are able to assign a neutral status to Asp213 and a, partially negatively charged status to Asp33 with reasonable confidence., Similar very short hydrogen bonds involving the active site glutamic acid, residues of thermolysin and carboxypeptidase A and the pro-R oxygen of, bound phosphonate inhibitors have been reported [Holden, H. M., Tronrud, D. E., Monzingo, A. F., Weaver, L. H., &amp; Matthews, B. W. (1987), Biochemistry 26, 8542-8553; Kim, H., &amp; Lipscomb, W. N. (1991) Biochemistry, 30, 8171-8180].(ABSTRACT TRUNCATED AT 400 WORDS)
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<StructureSection load='1ppl' size='340' side='right'caption='[[1ppl]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1ppl]] is a 1 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=1PPL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PPL 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]] 1.7&#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=1Z7:N-(3-METHYLBUTANOYL)-L-VALYL-N-{(1S)-1-[(R)-[(1R)-1-BENZYL-2-METHOXY-2-OXOETHOXY](HYDROXY)PHOSPHORYL]-3-METHYLBUTYL}-L-VALINAMIDE'>1Z7</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=XYS:XYLOPYRANOSE'>XYS</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=1ppl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ppl OCA], [https://pdbe.org/1ppl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ppl RCSB], [https://www.ebi.ac.uk/pdbsum/1ppl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ppl ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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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/pp/1ppl_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=1ppl 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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1PPL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with MAN, XYS and SO4 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1PPL OCA].
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*[[Penicillopepsin|Penicillopepsin]]
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*[[Pepsin|Pepsin]]
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==Reference==
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== References ==
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Crystallographic analysis of transition-state mimics bound to penicillopepsin: phosphorus-containing peptide analogues., Fraser ME, Strynadka NC, Bartlett PA, Hanson JE, James MN, Biochemistry. 1992 Jun 9;31(22):5201-14. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=1606144 1606144]
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<references/>
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[[Category: Penicillopepsin]]
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__TOC__
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[[Category: Single protein]]
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</StructureSection>
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[[Category: Fraser, M.E.]]
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[[Category: Large Structures]]
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[[Category: James, M.N.G.]]
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[[Category: Penicillium janthinellum]]
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[[Category: MAN]]
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[[Category: Fraser ME]]
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[[Category: SO4]]
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[[Category: James MNG]]
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[[Category: XYS]]
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[[Category: hydrolase(acid proteinase)]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 00:00:10 2007''
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Current revision

CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN: PHOSPHORUS-CONTAINING PEPTIDE ANALOGUES

PDB ID 1ppl

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