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1bxo

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ACID PROTEINASE (PENICILLOPEPSIN) (E.C.3.4.23.20) COMPLEX WITH PHOSPHONATE INHIBITOR: METHYL CYCLO[(2S)-2-[[(1R)-1-(N-(L-N-(3-METHYLBUTANOYL)VALYL-L-ASPARTYL)AMINO)-3-METHYLBUT YL] HYDROXYPHOSPHINYLOXY]-3-(3-AMINOMETHYL) PHENYLPROPANOATE

Structural highlights

1bxo is a 1 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 0.95Å
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.

Publication Abstract from PubMed

The design of inhibitors with enhanced potency against proteolytic enzymes has many applications for the treatment of human diseases. In addition to the optimization of chemical interactions between the enzyme and inhibitor, the binding affinity can be increased by constraining the inhibitor to the conformation that is recognized by the enzyme, thus lowering the entropic barrier to complex formation. We have structurally characterized the complexes of a macrocyclic pentapeptide inhibitor and its acyclic analogue with penicillopepsin, an aspartic proteinase, to study the effect of conformational constraint on the binding affinity. The phosphonate-based macrocycle PPi4 (Ki = 0.10 nM) is covalently linked at the P2-Asn and P1'-Phe side chains [nomenclature of Schechter and Berger, Biochim. Biophys. Res. Commun. (1967) 27, 157-162] via an amide bond, relative to the acyclic compound PPi3 (Ki = 42 nM). Comparisons of the high-resolution crystal structures of PPi4-penicillopepsin (0.95 A) and PPi3-penicillopepsin (1.45 A) reveal that the conformations of the inhibitors and their interactions with the enzyme are similar. The 420-fold increase in the binding affinity of PPi4 is attributed to a reduction in its conformational flexibility, thus providing the first rigorous measure of the entropic contribution to the binding energy in a protein-ligand complex and stressing the advantages of the design strategy.

Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes.,Khan AR, Parrish JC, Fraser ME, Smith WW, Bartlett PA, James MN Biochemistry. 1998 Dec 1;37(48):16839-45. PMID:9836576^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ Khan AR, Parrish JC, Fraser ME, Smith WW, Bartlett PA, James MN. Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes. Biochemistry. 1998 Dec 1;37(48):16839-45. PMID:9836576 doi:10.1021/bi9821364

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1bxo"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1bxo]] 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=1BXO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BXO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=PP7:METHYL+CYCLO[(2S)-2-[[(1R)-1-(N-(L-N-(3-METHYLBUTANOYL)VALYL-L-ASPARTYL)AMINO)-3-METHYLBUTYL]HYDROXYPHOSPHINYLOXY]-3-(3-AMINOMETHYL)PHENYLPROPANOATE'>PP7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.95&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Penicillopepsin Penicillopepsin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.20 3.4.23.20] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=PP7:METHYL+CYCLO[(2S)-2-[[(1R)-1-(N-(L-N-(3-METHYLBUTANOYL)VALYL-L-ASPARTYL)AMINO)-3-METHYLBUTYL]HYDROXYPHOSPHINYLOXY]-3-(3-AMINOMETHYL)PHENYLPROPANOATE'>PP7</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=1bxo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bxo OCA], [https://pdbe.org/1bxo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bxo RCSB], [https://www.ebi.ac.uk/pdbsum/1bxo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bxo 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]]
@@ Line 37: / Line 39: @@
 [[Category: Large Structures]]
 [[Category: Penicillium janthinellum]]
-[[Category: Penicillopepsin]]
+[[Category: Bartlett PA]]
-[[Category: Bartlett, P A]]
+[[Category: Fraser ME]]
-[[Category: Fraser, M E]]
+[[Category: James MNG]]
-[[Category: James, M N.G]]
+[[Category: Khan AR]]
-[[Category: Khan, A R]]
+[[Category: Parrish JC]]
-[[Category: Parrish, J C]]
+[[Category: Smith WW]]
-[[Category: Smith, W W]]
-[[Category: Hydrolase]]
-[[Category: Macrocycle]]
-[[Category: Phosphonate inhibitor]]

1bxo

From Proteopedia

Current revision

ACID PROTEINASE (PENICILLOPEPSIN) (E.C.3.4.23.20) COMPLEX WITH PHOSPHONATE INHIBITOR: METHYL CYCLO[(2S)-2-[[(1R)-1-(N-(L-N-(3-METHYLBUTANOYL)VALYL-L-ASPARTYL)AMINO)-3-METHYLBUT YL] HYDROXYPHOSPHINYLOXY]-3-(3-AMINOMETHYL) PHENYLPROPANOATE

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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