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==Crystal structure of human arginase I in complex with the inhibitor Me-ABH, Resolution 1.60 A, twinned structure== | |||
<StructureSection load='3sjt' size='340' side='right' caption='[[3sjt]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3sjt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SJT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SJT FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5AB:[(5S)-5-AMINO-5-CARBOXYHEXYL](TRIHYDROXY)BORATE'>5AB</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2aeb|2aeb]], [[3skk|3skk]], [[3sl0|3sl0]], [[3sl1|3sl1]], [[3gmz|3gmz]], [[3gn0|3gn0]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARG1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Arginase Arginase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3sjt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sjt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sjt RCSB], [http://www.ebi.ac.uk/pdbsum/3sjt PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN]] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:[http://omim.org/entry/207800 207800]]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.<ref>PMID:1463019</ref> <ref>PMID:7649538</ref> | |||
== Function == | |||
== | <div style="background-color:#fffaf0;"> | ||
== 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<ref>PMID:21728378</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
==See Also== | |||
*[[Arginase|Arginase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Arginase]] | [[Category: Arginase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Christianson, D W | [[Category: Christianson, D W]] | ||
[[Category: Costanzo, L Di | [[Category: Costanzo, L Di]] | ||
[[Category: 2-amino-6-borono-2-methylhexanoic acid]] | [[Category: 2-amino-6-borono-2-methylhexanoic acid]] | ||
[[Category: Abh inhibitor derivative]] | [[Category: Abh inhibitor derivative]] | ||
Revision as of 10:15, 21 December 2014
Crystal structure of human arginase I in complex with the inhibitor Me-ABH, Resolution 1.60 A, twinned structureCrystal structure of human arginase I in complex with the inhibitor Me-ABH, Resolution 1.60 A, twinned structure
Structural highlights
Disease[ARGI1_HUMAN] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:207800]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.[1] [2] FunctionPublication Abstract from PubMedArginase 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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