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| | ==Crystal structure of human carboxypeptidase O in complex with NvCI== | | ==Crystal structure of human carboxypeptidase O in complex with NvCI== |
| - | <StructureSection load='5mrv' size='340' side='right' caption='[[5mrv]], [[Resolution|resolution]] 1.85Å' scene=''> | + | <StructureSection load='5mrv' size='340' side='right'caption='[[5mrv]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mrv]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Four-tooth_nerite Four-tooth nerite] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MRV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MRV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mrv]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Nerita_versicolor Nerita versicolor]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MRV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MRV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.854Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CPO ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mrv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrv OCA], [http://pdbe.org/5mrv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mrv RCSB], [http://www.ebi.ac.uk/pdbsum/5mrv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrv ProSAT]</span></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=5mrv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrv OCA], [https://pdbe.org/5mrv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mrv RCSB], [https://www.ebi.ac.uk/pdbsum/5mrv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CBPO_HUMAN CBPO_HUMAN]] Carboxypeptidase which preferentially cleaves C-terminal acidic residues from peptides and proteins. Can also cleave C-terminal hydrophobic amino acids, with a preference for small residues over large residues.<ref>PMID:21921028</ref> [[http://www.uniprot.org/uniprot/MCPI_NERVS MCPI_NERVS]] Metallocarboxypeptidase inhibitor. Has an inhibitory effect on bovine CPA1 and CPB2, human CPA1, CPA2, CPA4, CPB1 and CPB2, and porcine CPB1. Does not inhibit D.melanogaster svr (carboxypeptidase D). Shows no activity against serine proteases subtilisin or bovine trypsin, cysteine protease papain, and aspartyl protease porcine pepsin.<ref>PMID:22294694</ref> [UniProtKB:P01075] | + | [https://www.uniprot.org/uniprot/CBPO_HUMAN CBPO_HUMAN] Carboxypeptidase which preferentially cleaves C-terminal acidic residues from peptides and proteins. Can also cleave C-terminal hydrophobic amino acids, with a preference for small residues over large residues.<ref>PMID:21921028</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Carboxypeptidase|Carboxypeptidase]] | + | *[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Four-tooth nerite]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Aviles, F X]] | + | [[Category: Nerita versicolor]] |
| - | [[Category: Fernandez-Alvarez, R]] | + | [[Category: Aviles FX]] |
| - | [[Category: Garcia-Guerrero, M C]] | + | [[Category: Fernandez-Alvarez R]] |
| - | [[Category: Garcia-Pardo, J]] | + | [[Category: Garcia-Guerrero MC]] |
| - | [[Category: Lorenzo, J]] | + | [[Category: Garcia-Pardo J]] |
| - | [[Category: Lyons, P]] | + | [[Category: Lorenzo J]] |
| - | [[Category: Reverter, D]] | + | [[Category: Lyons P]] |
| - | [[Category: Brush border enzyme]]
| + | [[Category: Reverter D]] |
| - | [[Category: Carboxypeptidase inhibitor]]
| + | |
| - | [[Category: Digestive metallocarboxypeptidase]]
| + | |
| - | [[Category: Food digestion]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
CBPO_HUMAN Carboxypeptidase which preferentially cleaves C-terminal acidic residues from peptides and proteins. Can also cleave C-terminal hydrophobic amino acids, with a preference for small residues over large residues.[1]
Publication Abstract from PubMed
Human metallocarboxypeptidase O (hCPO) is a recently discovered digestive enzyme localized to the apical membrane of intestinal epithelial cells. Unlike pancreatic metallocarboxypeptidases, hCPO is glycosylated and produced as an active enzyme with distinctive substrate specificity toward C-terminal (C-t) acidic residues. Here we present the crystal structure of hCPO at 1.85-A resolution, both alone and in complex with a carboxypeptidase inhibitor (NvCI) from the marine snail Nerita versicolor The structure provides detailed information regarding determinants of enzyme specificity, in particular Arg275, placed at the bottom of the substrate-binding pocket. This residue, located at "canonical" position 255, where it is Ile in human pancreatic carboxypeptidases A1 (hCPA1) and A2 (hCPA2) and Asp in B (hCPB), plays a dominant role in determining the preference of hCPO for acidic C-t residues. Site-directed mutagenesis to Asp and Ala changes the specificity to C-t basic and hydrophobic residues, respectively. The single-site mutants thus faithfully mimic the enzymatic properties of CPB and CPA, respectively. hCPO also shows a preference for Glu over Asp, probably as a consequence of a tighter fitting of the Glu side chain in its S1' substrate-binding pocket. This unique preference of hCPO, together with hCPA1, hCPA2, and hCPB, completes the array of C-t cleavages enabling the digestion of the dietary proteins within the intestine. Finally, in addition to activity toward small synthetic substrates and peptides, hCPO can also trim C-t extensions of proteins, such as epidermal growth factor, suggesting a role in the maturation and degradation of growth factors and bioactive peptides.
Crystal structure and mechanism of human carboxypeptidase O: Insights into its specific activity for acidic residues.,Garcia-Guerrero MC, Garcia-Pardo J, Berenguer E, Fernandez-Alvarez R, Barfi GB, Lyons PJ, Aviles FX, Huber R, Lorenzo J, Reverter D Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3932-E3939. doi:, 10.1073/pnas.1803685115. Epub 2018 Apr 10. PMID:29636417[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lyons PJ, Fricker LD. Carboxypeptidase O is a glycosylphosphatidylinositol-anchored intestinal peptidase with acidic amino acid specificity. J Biol Chem. 2011 Nov 11;286(45):39023-32. doi: 10.1074/jbc.M111.265819. Epub, 2011 Sep 15. PMID:21921028 doi:http://dx.doi.org/10.1074/jbc.M111.265819
- ↑ Garcia-Guerrero MC, Garcia-Pardo J, Berenguer E, Fernandez-Alvarez R, Barfi GB, Lyons PJ, Aviles FX, Huber R, Lorenzo J, Reverter D. Crystal structure and mechanism of human carboxypeptidase O: Insights into its specific activity for acidic residues. Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3932-E3939. doi:, 10.1073/pnas.1803685115. Epub 2018 Apr 10. PMID:29636417 doi:http://dx.doi.org/10.1073/pnas.1803685115
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