5f5g: Difference between revisions
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==Structure of E.Coli GlpG Y205F mutant complexed with peptidic inhibitor Ac-RMA-CHO in the DMPC/CHAPSO bicelle== | |||
<StructureSection load='5f5g' size='340' side='right'caption='[[5f5g]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5f5g]] 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=5F5G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F5G 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=5XU:(2~{S})-2-AZANYLPROPANAL'>5XU</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</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=5f5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f5g OCA], [https://pdbe.org/5f5g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f5g RCSB], [https://www.ebi.ac.uk/pdbsum/5f5g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f5g 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 == | |||
Intramembrane proteases signal by releasing proteins from the membrane, but despite their importance, their enzymatic mechanisms remain obscure. We probed rhomboid proteases with reversible, mechanism-based inhibitors that allow precise kinetic analysis and faithfully mimic the transition state structurally. Unexpectedly, inhibition by peptide aldehydes is non-competitive, revealing that in the Michaelis complex, substrate does not contact the catalytic center. Structural analysis in a membrane revealed that all extracellular loops of rhomboid make stabilizing interactions with substrate, but mainly through backbone interactions, explaining rhomboid's broad sequence selectivity. At the catalytic site, the tetrahedral intermediate lies covalently attached to the catalytic serine alone, with the oxyanion stabilized by unusual tripartite interactions with the side chains of H150, N154, and the backbone of S201. We also visualized unexpected substrate-enzyme interactions at the non-essential P2/P3 residues. These "extra" interactions foster potent rhomboid inhibition in living cells, thereby opening avenues for rational design of selective rhomboid inhibitors. | |||
Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis.,Cho S, Dickey SW, Urban S Mol Cell. 2016 Feb 4;61(3):329-40. doi: 10.1016/j.molcel.2015.12.022. Epub 2016, Jan 21. PMID:26805573<ref>PMID:26805573</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5f5g" 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: Dickey SW]] | |||
[[Category: Urban S]] | |||
Latest revision as of 11:48, 12 July 2023
Structure of E.Coli GlpG Y205F mutant complexed with peptidic inhibitor Ac-RMA-CHO in the DMPC/CHAPSO bicelleStructure of E.Coli GlpG Y205F mutant complexed with peptidic inhibitor Ac-RMA-CHO in the DMPC/CHAPSO bicelle
Structural highlights
FunctionGLPG_ECOLI Rhomboid-type serine protease that catalyzes intramembrane proteolysis.[1] [2] Publication Abstract from PubMedIntramembrane proteases signal by releasing proteins from the membrane, but despite their importance, their enzymatic mechanisms remain obscure. We probed rhomboid proteases with reversible, mechanism-based inhibitors that allow precise kinetic analysis and faithfully mimic the transition state structurally. Unexpectedly, inhibition by peptide aldehydes is non-competitive, revealing that in the Michaelis complex, substrate does not contact the catalytic center. Structural analysis in a membrane revealed that all extracellular loops of rhomboid make stabilizing interactions with substrate, but mainly through backbone interactions, explaining rhomboid's broad sequence selectivity. At the catalytic site, the tetrahedral intermediate lies covalently attached to the catalytic serine alone, with the oxyanion stabilized by unusual tripartite interactions with the side chains of H150, N154, and the backbone of S201. We also visualized unexpected substrate-enzyme interactions at the non-essential P2/P3 residues. These "extra" interactions foster potent rhomboid inhibition in living cells, thereby opening avenues for rational design of selective rhomboid inhibitors. Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis.,Cho S, Dickey SW, Urban S Mol Cell. 2016 Feb 4;61(3):329-40. doi: 10.1016/j.molcel.2015.12.022. Epub 2016, Jan 21. PMID:26805573[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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