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Title: Open-cap Conformation of Intramembrane Protease GlpG

Abstract

The active sites of intramembrane proteases are positioned in the lipid bilayer to facilitate peptide bond hydrolysis in the membrane. Previous crystallographic analysis of Escherichia coli GlpG, an intramembrane protease of the rhomboid family, has revealed an internal and hydrophilic active site in an apparently closed conformation. Here we describe the crystal structure of GlpG in a more open conformation, where the capping loop L5 has been lifted, exposing the previously buried and catalytically essential Ser-201 to outside aqueous solution. A water molecule now moves into the putative oxyanion hole that is constituted of a main-chain amide (Ser-201) and two conserved side chains (His-150 and Asn-154). The loop movement also destabilizes a hydrophobic side chain (Phe-245) previously buried between transmembrane helices S2 and S5 and creates a side portal from the lipid to protease active site. These results provide insights into the conformational plasticity of GlpG to accommodate substrate binding and catalysis and into the chirality of the reaction intermediate.

Authors:
;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930296
Report Number(s):
BNL-81001-2008-JA
TRN: US200822%%1453
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 104; Journal Issue: 7
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; AMIDES; AQUEOUS SOLUTIONS; CATALYSIS; CHIRALITY; CRYSTAL STRUCTURE; ESCHERICHIA COLI; HOLES; HYDROLYSIS; LIPIDS; MOLECULES; PEPTIDES; PLASTICITY; REACTION INTERMEDIATES; SUBSTRATES; WATER; national synchrotron light source

Citation Formats

Wang,Y., and Ha, Y.. Open-cap Conformation of Intramembrane Protease GlpG. United States: N. p., 2007. Web. doi:10.1073/pnas.0611080104.
Wang,Y., & Ha, Y.. Open-cap Conformation of Intramembrane Protease GlpG. United States. doi:10.1073/pnas.0611080104.
Wang,Y., and Ha, Y.. Mon . "Open-cap Conformation of Intramembrane Protease GlpG". United States. doi:10.1073/pnas.0611080104.
@article{osti_930296,
title = {Open-cap Conformation of Intramembrane Protease GlpG},
author = {Wang,Y. and Ha, Y.},
abstractNote = {The active sites of intramembrane proteases are positioned in the lipid bilayer to facilitate peptide bond hydrolysis in the membrane. Previous crystallographic analysis of Escherichia coli GlpG, an intramembrane protease of the rhomboid family, has revealed an internal and hydrophilic active site in an apparently closed conformation. Here we describe the crystal structure of GlpG in a more open conformation, where the capping loop L5 has been lifted, exposing the previously buried and catalytically essential Ser-201 to outside aqueous solution. A water molecule now moves into the putative oxyanion hole that is constituted of a main-chain amide (Ser-201) and two conserved side chains (His-150 and Asn-154). The loop movement also destabilizes a hydrophobic side chain (Phe-245) previously buried between transmembrane helices S2 and S5 and creates a side portal from the lipid to protease active site. These results provide insights into the conformational plasticity of GlpG to accommodate substrate binding and catalysis and into the chirality of the reaction intermediate.},
doi = {10.1073/pnas.0611080104},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 7,
volume = 104,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}