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==Crystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithine== | |||
<StructureSection load='3p8e' size='340' side='right' caption='[[3p8e]], [[Resolution|resolution]] 2.49Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3p8e]] 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=3P8E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3P8E FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LN7:N~5~-[(1S)-1-AMINOPENTYL]-L-ORNITHINE'>LN7</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3i2e|3i2e]], [[3i4a|3i4a]], [[3p8p|3p8p]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDAH, DDAH1 ([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/Dimethylargininase Dimethylargininase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.18 3.5.3.18] </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=3p8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3p8e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3p8e RCSB], [http://www.ebi.ac.uk/pdbsum/3p8e PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
C-Alkyl amidine analogues of asymmetric N(omega),N(omega)-dimethyl-L-arginine are dual-targeted inhibitors of both human DDAH-1 and nitric oxide (NO) synthase, and provide a promising scaffold for the development of therapeutics to control NO overproduction in a variety of pathologies including septic shock and some cancers. Using a two-part click-chemistry-mediated activity probe, a homologated series of C-alkyl amidines were ranked for their ability to inhibit DDAH-1 within cultured HEK 293T cells. N(5)-(1-Iminopentyl)-L-ornithine was determined to be the most potent compound in vitro (K(d)=7 muM) as well as in cultured cells, and the binding conformation and covalent reversible mode of inhibition was investigated by comparison of interactions made with DDAH-1 and a catalytically inactive C274S variant, as gauged by X-ray crystallography and isothermal titration calorimetry. By interrupting the ability of the inhibitor to form a covalent bond, the contribution of this interaction could be estimated. These results suggest that further stabilization of the covalent adduct is a promising strategy for lead optimization in the design of effective reagents to block NO synthesis. | |||
Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1.,Lluis M, Wang Y, Monzingo AF, Fast W, Robertus JD ChemMedChem. 2010 Oct 26. PMID:20979083<ref>PMID:20979083</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Dimethylargininase]] | [[Category: Dimethylargininase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Fast, W | [[Category: Fast, W]] | ||
[[Category: Lluis, M | [[Category: Lluis, M]] | ||
[[Category: Monzingo, A F | [[Category: Monzingo, A F]] | ||
[[Category: Robertus, J D | [[Category: Robertus, J D]] | ||
[[Category: Wang, Y | [[Category: Wang, Y]] | ||
[[Category: Ddah]] | [[Category: Ddah]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Nitric oxide synthase regulation]] | [[Category: Nitric oxide synthase regulation]] | ||
Revision as of 10:19, 19 December 2014
Crystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithineCrystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithine
Structural highlights
Publication Abstract from PubMedC-Alkyl amidine analogues of asymmetric N(omega),N(omega)-dimethyl-L-arginine are dual-targeted inhibitors of both human DDAH-1 and nitric oxide (NO) synthase, and provide a promising scaffold for the development of therapeutics to control NO overproduction in a variety of pathologies including septic shock and some cancers. Using a two-part click-chemistry-mediated activity probe, a homologated series of C-alkyl amidines were ranked for their ability to inhibit DDAH-1 within cultured HEK 293T cells. N(5)-(1-Iminopentyl)-L-ornithine was determined to be the most potent compound in vitro (K(d)=7 muM) as well as in cultured cells, and the binding conformation and covalent reversible mode of inhibition was investigated by comparison of interactions made with DDAH-1 and a catalytically inactive C274S variant, as gauged by X-ray crystallography and isothermal titration calorimetry. By interrupting the ability of the inhibitor to form a covalent bond, the contribution of this interaction could be estimated. These results suggest that further stabilization of the covalent adduct is a promising strategy for lead optimization in the design of effective reagents to block NO synthesis. Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1.,Lluis M, Wang Y, Monzingo AF, Fast W, Robertus JD ChemMedChem. 2010 Oct 26. PMID:20979083[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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