Crystal structure of a rhomboid family intramembrane protease

Nature. 2006 Nov 9;444(7116):179-80. doi: 10.1038/nature05255. Epub 2006 Oct 11.


Escherichia coli GlpG is an integral membrane protein that belongs to the widespread rhomboid protease family. Rhomboid proteases, like site-2 protease (S2P) and gamma-secretase, are unique in that they cleave the transmembrane domain of other membrane proteins. Here we describe the 2.1 A resolution crystal structure of the GlpG core domain. This structure contains six transmembrane segments. Residues previously shown to be involved in catalysis, including a Ser-His dyad, and several water molecules are found at the protein interior at a depth below the membrane surface. This putative active site is accessible by substrate through a large 'V-shaped' opening that faces laterally towards the lipid, but is blocked by a half-submerged loop structure. These observations indicate that, in intramembrane proteolysis, the scission of peptide bonds takes place within the hydrophobic environment of the membrane bilayer. The crystal structure also suggests a gating mechanism for GlpG that controls substrate access to its hydrophilic active site.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Catalysis
  • Cell Membrane / enzymology*
  • Crystallization
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / classification*
  • DNA-Binding Proteins / metabolism
  • Endopeptidases / chemistry*
  • Endopeptidases / classification*
  • Endopeptidases / metabolism
  • Escherichia coli / enzymology*
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / classification*
  • Escherichia coli Proteins / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Membrane Proteins / chemistry*
  • Membrane Proteins / classification*
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Protein Structure, Tertiary
  • Substrate Specificity
  • Water / chemistry
  • Water / metabolism


  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • GlpG protein, E coli
  • Membrane Proteins
  • Water
  • Endopeptidases

Associated data

  • PDB/2IC8