View source for 6vj9


==Crystal structure of GlpG in complex with peptide boronate inhibitor==
<StructureSection load='6vj9' size='340' side='right'caption='[[6vj9]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6vj9]] 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=6VJ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VJ9 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]] 2.3&#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=B2A:ALANINE+BORONIC+ACID'>B2A</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=6vj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vj9 OCA], [https://pdbe.org/6vj9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vj9 RCSB], [https://www.ebi.ac.uk/pdbsum/6vj9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vj9 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 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 &gt;10-fold, and solved high-resolution structures to discover that boronates enhance inhibition &gt;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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6vj9" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Drosophila melanogaster]]
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Cho S]]
[[Category: Urban S]]