Rhomboids are intramembrane serine peptidases conserved in all kingdoms of life. 
Their general role is to cleave integral membrane proteins to release signalling 
molecules. These signals, when disrupted, can contribute to various diseases. 
Crystal structures of H. influenzae (hiGlpG) and E. coli GlpG (ecGlpG) rhomboids 
have revealed a structure with six transmembrane helices and a Ser-His catalytic 
dyad buried within the membrane. One emerging issue was the identification of 
the mobile element in the protein that allows substrate docking. It has been 
proposed that the substrate entry gate is composed of helix 5 and loop 5. The 
present review studies the structures of these two orthologs. In ecGlpG 
structures, different conformations of loop 5 and helix 5 are observed. Open and 
closed conformations of ecGlpG structures are compared with each other and with 
hiGlpG, surveying differences in hydrophobic interactions within loop 5 and 
helix 5. Furthermore, a comparison of the ecGlpG and hiGlpG structures reveals 
differences in loop 4. Overall, less variation is observed in loop 4, suggesting 
this region acts as an anchor for the substrate gate. Functional and regulatory 
implications of these variations are discussed.