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==Crystal structure of human testis Angiotensin-1 converting enzyme in complex with Sampatrilat-Asp.== | |||
<StructureSection load='6f9u' size='340' side='right'caption='[[6f9u]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f9u]] 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=6F9U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F9U 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]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=BO3:BORIC+ACID'>BO3</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=D0W:(3~{S})-3-acetamido-4-[[(2~{S})-2-[[1-[[(2~{S})-3-(4-hydroxyphenyl)-1-oxidanyl-1-oxidanylidene-propan-2-yl]carbamoyl]cyclopentyl]methyl]-3-oxidanyl-3-oxidanylidene-propyl]amino]-4-oxidanylidene-butanoic+acid'>D0W</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6f9u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f9u OCA], [https://pdbe.org/6f9u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f9u RCSB], [https://www.ebi.ac.uk/pdbsum/6f9u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f9u ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Angiotensin-1 converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight-binding inhibitor of ACE, Ki =13.8 nM and 171.9 nM for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486-2494] was 12.4-fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a non-specific and lower micromolar affinity inhibitor. Here we report a detailed three-dimensional structural analysis of sampatrilat and samAsp binding to ACE using high resolution crystal structures elucidated by X-ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H-bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE. This article is protected by copyright. All rights reserved. | |||
Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE: a molecular basis for domain-selectivity.,Cozier GE, Schwager SL, Sharma RK, Chibale K, Sturrock ED, Acharya KR FEBS J. 2018 Feb 24. doi: 10.1111/febs.14421. PMID:29476645<ref>PMID:29476645</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Acharya | <div class="pdbe-citations 6f9u" style="background-color:#fffaf0;"></div> | ||
[[Category: Cozier | |||
==See Also== | |||
*[[Angiotensin-Converting Enzyme 3D structures|Angiotensin-Converting Enzyme 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Acharya KR]] | |||
[[Category: Cozier GE]] | |||