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| | ==Crystal structure of the dimethylarginine dimethylaminohydrolase adduct with N5-(1-imino-2-chloroethyl)-L-lysine== | | ==Crystal structure of the dimethylarginine dimethylaminohydrolase adduct with N5-(1-imino-2-chloroethyl)-L-lysine== |
| - | <StructureSection load='6dge' size='340' side='right' caption='[[6dge]], [[Resolution|resolution]] 1.91Å' scene=''> | + | <StructureSection load='6dge' size='340' side='right'caption='[[6dge]], [[Resolution|resolution]] 1.91Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dge]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DGE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dge]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DGE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DGE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GBG:N~6~-[(1E)-2-chloroethanimidoyl]-L-lysine'>GBG</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]] 1.91Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3i2e|3i2e]], [[3p8e|3p8e]], [[3i4a|3i4a]], [[3p8p|3p8p]], [[2jai|2jai]], [[2jaj|2jaj]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GBG:N~6~-[(1E)-2-chloroethanimidoyl]-L-lysine'>GBG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDAH1, DDAH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6dge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dge OCA], [https://pdbe.org/6dge PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dge RCSB], [https://www.ebi.ac.uk/pdbsum/6dge PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dge ProSAT]</span></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=6dge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dge OCA], [http://pdbe.org/6dge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dge RCSB], [http://www.ebi.ac.uk/pdbsum/6dge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dge ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dimethylargininase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Burstein-Teitelbaum, G]] | + | [[Category: Burstein-Teitelbaum G]] |
| - | [[Category: Er, J A.V]] | + | [[Category: Er JAV]] |
| - | [[Category: Fast, W]] | + | [[Category: Fast W]] |
| - | [[Category: Monzingo, A F]] | + | [[Category: Monzingo AF]] |
| - | [[Category: Tuley, A]] | + | [[Category: Tuley A]] |
| - | [[Category: Covalent inhibitor]]
| + | |
| - | [[Category: Enzyme adduct]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| 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 PubMed
Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1) can control endogenous nitric oxide production. A time-dependent covalent inactivator of DDAH1, N(5)-(1-imino-2-chloroethyl)-l-ornithine ( KI = 1.3 muM, kinact = 0.34 min(-1)), was conceptually dissected into two fragments and each characterized separately: l-norvaline ( Ki = 470 muM) and 2-chloroacetamidine ( KI = 310 muM, kinact = 4.0 min(-1)). This analysis suggested that the two fragments were not linked in a manner that allows either to reach full affinity or reactivity, prompting the synthesis and characterization of three analogues: two that mimic the dimethylation status of the substrate, N(5)-(1-imino-2-chloroisopropyl)-l-ornithine ( kinact /KI = 208 M(-1) s(-1)) and N(5)-(1-imino-2-chlorisopropyl)-l-lysine ( kinact /KI = 440 M(-1) s(-1)), and one that lengthens the linker beyond that found in the substrate, N(5)-(1-imino-2-chloroethyl)-l-lysine (Cl-NIL, KI = 0.19 muM, kinact = 0.22 min(-1)). Cl-NIL is one of the most potent inhibitors reported for DDAH1, inactivates with a second order rate constant (1.9 x 10(4) M(-1) s(-1)) larger than the catalytic efficiency of DDAH1 for its endogenous substrate (1.6 x 10(2) M(-1) s(-1)), and has a partition ratio of 1 with a >100000-fold selectivity for DDAH1 over arginase. An activity-based protein-profiling probe is used to show inhibition of DDAH1 within cultured HEK293T cells (IC50 = 10 muM) with cytotoxicity appearing only at higher concentrations (ED50 = 118 muM). A 1.91 A resolution X-ray crystal structure reveals specific interactions made with DDAH1 upon covalent inactivation by Cl-NIL. Dissecting a covalent inactivator and analysis of its constituent fragments proved useful for the design and optimization of this potent and effective DDAH1 inhibitor.
Dissection, Optimization, and Structural Analysis of a Covalent Irreversible DDAH1 Inhibitor.,Burstein-Teitelbaum G, Er JAV, Monzingo AF, Tuley A, Fast W Biochemistry. 2018 Jul 20. doi: 10.1021/acs.biochem.8b00554. PMID:29983043[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Burstein-Teitelbaum G, Er JAV, Monzingo AF, Tuley A, Fast W. Dissection, Optimization, and Structural Analysis of a Covalent Irreversible DDAH1 Inhibitor. Biochemistry. 2018 Jul 20. doi: 10.1021/acs.biochem.8b00554. PMID:29983043 doi:http://dx.doi.org/10.1021/acs.biochem.8b00554
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