6dge: Difference between revisions
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New page: '''Unreleased structure''' The entry 6dge is ON HOLD Authors: Monzingo, A.F., Burstein-Teitelbaum, G., Er, J.A.V., Tuley, A., Fast, W. Description: Crystal structure of the dimethylarg... |
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==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=''> | |||
== Structural highlights == | |||
<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='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='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='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> | |||
</table> | |||
== 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;"> | |||
== 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<ref>PMID:29983043</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6dge" style="background-color:#fffaf0;"></div> | ||
[[Category: Burstein-Teitelbaum | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: Monzingo | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Burstein-Teitelbaum G]] | |||
[[Category: Er JAV]] | |||
[[Category: Fast W]] | |||
[[Category: Monzingo AF]] | |||
[[Category: Tuley A]] | |||
