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| | <StructureSection load='3sl0' size='340' side='right'caption='[[3sl0]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='3sl0' size='340' side='right'caption='[[3sl0]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3sl0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SL0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SL0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3sl0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SL0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SL0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FB5:2-(DIFLUOROMETHYL)-6-(DIHYDROXYBORANYL)-L-NORLEUCINE'>FB5</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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]] 1.997Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3mmr|3mmr]], [[3sl1|3sl1]], [[3sjt|3sjt]], [[3skk|3skk]], [[3gmz|3gmz]], [[3gn0|3gn0]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FB5:2-(DIFLUOROMETHYL)-6-(DIHYDROXYBORANYL)-L-NORLEUCINE'>FB5</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFI0320w ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Arginase Arginase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.1 3.5.3.1] </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=3sl0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sl0 OCA], [https://pdbe.org/3sl0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sl0 RCSB], [https://www.ebi.ac.uk/pdbsum/3sl0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sl0 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=3sl0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sl0 OCA], [https://pdbe.org/3sl0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sl0 RCSB], [https://www.ebi.ac.uk/pdbsum/3sl0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sl0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ARGI_PLAF7 ARGI_PLAF7] Catalyzes the hydrolysis of L-arginine into urea and L-ornithine, which is a precursor for polyamine biosynthesis (PubMed:15843155, PubMed:19456858, PubMed:20527960, PubMed:21728378). May play a role in parasite intra-hepatic development during the host liver stage (By similarity).[UniProtKB:A0A509AF89]<ref>PMID:15843155</ref> <ref>PMID:19456858</ref> <ref>PMID:20527960</ref> <ref>PMID:21728378</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Arginase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Plaf7]] | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Christianson, D W]] | + | [[Category: Christianson DW]] |
| - | [[Category: Dowling, D P]] | + | [[Category: Dowling DP]] |
| - | [[Category: Ilies, M]] | + | [[Category: Ilies M]] |
| - | [[Category: Arginase fold]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Metallohydrolase]]
| + | |
| Structural highlights
Function
ARGI_PLAF7 Catalyzes the hydrolysis of L-arginine into urea and L-ornithine, which is a precursor for polyamine biosynthesis (PubMed:15843155, PubMed:19456858, PubMed:20527960, PubMed:21728378). May play a role in parasite intra-hepatic development during the host liver stage (By similarity).[UniProtKB:A0A509AF89][1] [2] [3] [4]
Publication Abstract from PubMed
Arginase is a binuclear manganese metalloenzyme that hydrolyzes l-arginine to form l-ornithine and urea, and aberrant arginase activity is implicated in various diseases such as erectile dysfunction, asthma, atherosclerosis, and cerebral malaria. Accordingly, arginase inhibitors may be therapeutically useful. Continuing our efforts to expand the chemical space of arginase inhibitor design and inspired by the binding of 2-(difluoromethyl)-l-ornithine to human arginase I, we now report the first study of the binding of alpha,alpha-disubstituted amino acids to arginase. Specifically, we report the design, synthesis, and assay of racemic 2-amino-6-borono-2-methylhexanoic acid and racemic 2-amino-6-borono-2-(difluoromethyl)hexanoic acid. X-ray crystal structures of human arginase I and Plasmodium falciparum arginase complexed with these inhibitors reveal the exclusive binding of the l-stereoisomer; the additional alpha-substituent of each inhibitor is readily accommodated and makes new intermolecular interactions in the outer active site of each enzyme. Therefore, this work highlights a new region of the protein surface that can be targeted for additional affinity interactions, as well as the first comparative structural insights on inhibitor discrimination between a human and a parasitic arginase.
Binding of alpha,alpha-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design.,Ilies M, Di Costanzo L, Dowling DP, Thorn KJ, Christianson DW J Med Chem. 2011 Jul 18. PMID:21728378[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Müller IB, Walter RD, Wrenger C. Structural metal dependency of the arginase from the human malaria parasite Plasmodium falciparum. Biol Chem. 2005 Feb;386(2):117-26. PMID:15843155 doi:10.1515/BC.2005.015
- ↑ Wells GA, Muller IB, Wrenger C, Louw AI. The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404. FEBS J. 2009 Jul;276(13):3517-30. Epub 2009 May 18. PMID:19456858 doi:10.1111/j.1742-4658.2009.07073.x
- ↑ Dowling DP, Ilies M, Olszewski KL, Portugal S, Mota MM, Llinas M, Christianson DW. Crystal Structure of Arginase from Plasmodium falciparum and Implications for l-Arginine Depletion in Malarial Infection . Biochemistry. 2010 Jun 9. PMID:20527960 doi:10.1021/bi100390z
- ↑ Ilies M, Di Costanzo L, Dowling DP, Thorn KJ, Christianson DW. Binding of alpha,alpha-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design. J Med Chem. 2011 Jul 18. PMID:21728378 doi:10.1021/jm200443b
- ↑ Ilies M, Di Costanzo L, Dowling DP, Thorn KJ, Christianson DW. Binding of alpha,alpha-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design. J Med Chem. 2011 Jul 18. PMID:21728378 doi:10.1021/jm200443b
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