View source for 5mtf


==A modular route to novel potent and selective inhibitors of rhomboid intramembrane proteases==
<StructureSection load='5mtf' size='340' side='right'caption='[[5mtf]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5mtf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_S88 Escherichia coli S88] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MTF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MTF 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]] 1.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=BNG:B-NONYLGLUCOSIDE'>BNG</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=W6Q:(2~{R},3~{S})-3-azanyl-~{N}-[(2,5-dimethylphenyl)methyl]-2-oxidanyl-butanamide'>W6Q</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=5mtf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mtf OCA], [https://pdbe.org/5mtf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mtf RCSB], [https://www.ebi.ac.uk/pdbsum/5mtf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mtf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GLPG_ECOLI GLPG_ECOLI] Rhomboid-type serine protease that catalyzes intramembrane proteolysis.<ref>PMID:17099694</ref> <ref>PMID:16216077</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl alpha-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.

General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases.,Ticha A, Stanchev S, Vinothkumar KR, Mikles DC, Pachl P, Began J, Skerle J, Svehlova K, Nguyen MTN, Verhelst SHL, Johnson DC, Bachovchin DA, Lepsik M, Majer P, Strisovsky K Cell Chem Biol. 2017 Oct 12. pii: S2451-9456(17)30351-3. doi:, 10.1016/j.chembiol.2017.09.007. PMID:29107700<ref>PMID:29107700</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5mtf" style="background-color:#fffaf0;"></div>

==See Also==
*[[Rhomboid protease|Rhomboid protease]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli S88]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Bachovchin D]]
[[Category: Johnson D]]
[[Category: Lepsik M]]
[[Category: Majer P]]
[[Category: Mikles DC]]
[[Category: Nguyen MTN]]
[[Category: Pachl P]]
[[Category: Stanchev S]]
[[Category: Strisovsky K]]
[[Category: Svehlova K]]
[[Category: Ticha A]]
[[Category: Verhelst SHL]]
[[Category: Vinothkumar KR]]