3p8e: Difference between revisions
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==Crystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithine== | ==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=''> | <StructureSection load='3p8e' size='340' side='right'caption='[[3p8e]], [[Resolution|resolution]] 2.49Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3p8e]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3p8e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. 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 [https://proteopedia.org/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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3i2e|3i2e]], [[3i4a|3i4a]], [[3p8p|3p8p]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDAH, DDAH1 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDAH, DDAH1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dimethylargininase Dimethylargininase], with EC number [https://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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3p8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3p8e OCA], [https://pdbe.org/3p8e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3p8e RCSB], [https://www.ebi.ac.uk/pdbsum/3p8e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3p8e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/DDAH1_HUMAN DDAH1_HUMAN]] Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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[[Category: Dimethylargininase]] | [[Category: Dimethylargininase]] | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Fast, W]] | [[Category: Fast, W]] | ||
[[Category: Lluis, M]] | [[Category: Lluis, M]] | ||
Revision as of 14:24, 18 May 2022
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
Function[DDAH1_HUMAN] Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation. 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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