3p8p: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| (9 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal Structure of Human Dimethylarginine Dimethylaminohydrolase-1 (DDAH-1) variant C274S bound with N5-(1-iminopentyl)-L-ornithine== | |||
<StructureSection load='3p8p' size='340' side='right'caption='[[3p8p]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3p8p]] is a 2 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=3P8P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3P8P 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LN6:N~5~-[(1E)-PENTANIMIDOYL]-L-ORNITHINE'>LN6</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=3p8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3p8p OCA], [https://pdbe.org/3p8p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3p8p RCSB], [https://www.ebi.ac.uk/pdbsum/3p8p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3p8p 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 == | |||
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> | |||
<div class="pdbe-citations 3p8p" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Fast W]] | |||
[[Category: Lluis M]] | |||
[[Category: Monzingo AF]] | |||
[[Category: Robertus JD]] | |||
[[Category: Wang Y]] | |||
