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==Crystal structure of Leishmania mexicana arginase in complex with inhibitor ABHPE== | ==Crystal structure of Leishmania mexicana arginase in complex with inhibitor ABHPE== | ||
<StructureSection load='5hj9' size='340' side='right' caption='[[5hj9]], [[Resolution|resolution]] 1.28Å' scene=''> | <StructureSection load='5hj9' size='340' side='right'caption='[[5hj9]], [[Resolution|resolution]] 1.28Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5hj9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HJ9 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5hj9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_mexicana Leishmania mexicana]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HJ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HJ9 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X7A:[(5R)-5-AMINO-5-CARBOXY-7-(PIPERIDIN-1-YL)HEPTYL](TRIHYDROXY)BORATE(1-)'>X7A</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.28Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X7A:[(5R)-5-AMINO-5-CARBOXY-7-(PIPERIDIN-1-YL)HEPTYL](TRIHYDROXY)BORATE(1-)'>X7A</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=5hj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hj9 OCA], [https://pdbe.org/5hj9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hj9 RCSB], [https://www.ebi.ac.uk/pdbsum/5hj9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hj9 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/Q6TUJ5_LEIME Q6TUJ5_LEIME] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Leishmania arginase is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme initiates de novo polyamine biosynthesis by catalyzing the hydrolysis of L-arginine to generate L-ornithine and urea. The product L-ornithine subsequently undergoes decarboxylation to yield putrescine, which in turn is utilized for spermidine biosynthesis. Polyamines such as spermidine are essential for the growth and survival of the parasite, so inhibition of enzymes in the polyamine-biosynthetic pathway comprises an effective strategy for treating parasitic infections. To this end, two X-ray crystal structures of L. mexicana arginase complexed with alpha,alpha-disubstituted boronic amino-acid inhibitors based on the molecular scaffold of 2-(S)-amino-6-boronohexanoic acid are now reported. Structural comparisons with human and parasitic arginase complexes reveal interesting differences in the binding modes of the additional alpha-substituents, i.e. the D side chains, of these inhibitors. Subtle differences in the three-dimensional contours of the outer active-site rims among arginases from different species lead to different conformations of the D side chains and thus different inhibitor-affinity trends. The structures suggest that it is possible to maintain affinity while fine-tuning intermolecular interactions of the D side chain of alpha,alpha-disubstituted boronic amino-acid inhibitors in the search for isozyme-specific and species-specific arginase inhibitors. | |||
Crystal structures of Leishmania mexicana arginase complexed with alpha,alpha-disubstituted boronic amino-acid inhibitors.,Hai Y, Christianson DW Acta Crystallogr F Struct Biol Commun. 2016 Apr;72(Pt 4):300-6. doi:, 10.1107/S2053230X16003630. Epub 2016 Mar 16. PMID:27050264<ref>PMID:27050264</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5hj9" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Arginase 3D structures|Arginase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Leishmania mexicana]] | ||
[[Category: | [[Category: Christianson DW]] | ||
[[Category: | [[Category: Hai Y]] | ||
Latest revision as of 10:38, 9 August 2023
Crystal structure of Leishmania mexicana arginase in complex with inhibitor ABHPECrystal structure of Leishmania mexicana arginase in complex with inhibitor ABHPE
Structural highlights
FunctionPublication Abstract from PubMedLeishmania arginase is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme initiates de novo polyamine biosynthesis by catalyzing the hydrolysis of L-arginine to generate L-ornithine and urea. The product L-ornithine subsequently undergoes decarboxylation to yield putrescine, which in turn is utilized for spermidine biosynthesis. Polyamines such as spermidine are essential for the growth and survival of the parasite, so inhibition of enzymes in the polyamine-biosynthetic pathway comprises an effective strategy for treating parasitic infections. To this end, two X-ray crystal structures of L. mexicana arginase complexed with alpha,alpha-disubstituted boronic amino-acid inhibitors based on the molecular scaffold of 2-(S)-amino-6-boronohexanoic acid are now reported. Structural comparisons with human and parasitic arginase complexes reveal interesting differences in the binding modes of the additional alpha-substituents, i.e. the D side chains, of these inhibitors. Subtle differences in the three-dimensional contours of the outer active-site rims among arginases from different species lead to different conformations of the D side chains and thus different inhibitor-affinity trends. The structures suggest that it is possible to maintain affinity while fine-tuning intermolecular interactions of the D side chain of alpha,alpha-disubstituted boronic amino-acid inhibitors in the search for isozyme-specific and species-specific arginase inhibitors. Crystal structures of Leishmania mexicana arginase complexed with alpha,alpha-disubstituted boronic amino-acid inhibitors.,Hai Y, Christianson DW Acta Crystallogr F Struct Biol Commun. 2016 Apr;72(Pt 4):300-6. doi:, 10.1107/S2053230X16003630. Epub 2016 Mar 16. PMID:27050264[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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