6xro: Difference between revisions
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==Crystal structure of GlpG in complex with peptide boronate inhibitor, Ac-KRFRSMQYSA-B(OH)2== | |||
<StructureSection load='6xro' size='340' side='right'caption='[[6xro]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6xro]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster] and [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XRO 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]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B2A:ALANINE+BORONIC+ACID'>B2A</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=6xro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xro OCA], [https://pdbe.org/6xro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xro RCSB], [https://www.ebi.ac.uk/pdbsum/6xro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xro ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites. | |||
Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria.,Gandhi S, Baker RP, Cho S, Stanchev S, Strisovsky K, Urban S Cell Chem Biol. 2020 Aug 31. pii: S2451-9456(20)30333-0. doi:, 10.1016/j.chembiol.2020.08.011. PMID:32888502<ref>PMID:32888502</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6xro" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Rhomboid protease|Rhomboid protease]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Drosophila melanogaster]] | |||
[[Category: Escherichia coli]] | |||
[[Category: Large Structures]] | |||
[[Category: Cho S]] | |||
[[Category: Urban S]] | |||
