3zot Citations

Structure of Rhomboid Protease in Complex with β-Lactam Inhibitors Defines the S2' Cavity.

OpenAccess logo Structure (2013)
Related entries: 3zmh, 3zmi, 3zmj

Cited: 7 times
EuropePMC logo PMID: 23665170


Rhomboids are evolutionarily conserved serine proteases that cleave transmembrane proteins within the membrane. The increasing number of known rhomboid functions in prokaryotes and eukaryotes makes them attractive drug targets. Here, we describe structures of the Escherichia coli rhomboid GlpG in complex with β-lactam inhibitors. The inhibitors form a single bond to the catalytic serine and the carbonyl oxygen of the inhibitor faces away from the oxyanion hole. The hydrophobic N-substituent of β-lactam inhibitors points into a cavity within the enzyme, providing a structural explanation for the specificity of β-lactams on rhomboid proteases. This same cavity probably represents the S2' substrate binding site of GlpG. We suggest that the structural changes in β-lactam inhibitor binding reflect the state of the enzyme at an initial stage of substrate binding to the active site. The structural insights from these enzyme-inhibitor complexes provide a starting point for structure-based design for rhomboid inhibitors.

Reviews citing this publication (4)

  1. Intramembrane proteases as drug targets. Verhelst SHL. FEBS J. 284 1489-1502 (2017)
  2. Rhomboid protease inhibitors: Emerging tools and future therapeutics. Strisovsky K. Semin. Cell Dev. Biol. 60 52-62 (2016)
  3. The rhomboid-like superfamily: molecular mechanisms and biological roles. Freeman M. Annu. Rev. Cell Dev. Biol. 30 235-254 (2014)
  4. Intramembrane proteolysis by rhomboids: catalytic mechanisms and regulatory principles. Vinothkumar KR, Freeman M. Curr. Opin. Struct. Biol. 23 851-858 (2013)

Articles citing this publication (3)

  1. Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures. Zoll S, Stanchev S, Began J, Skerle J, Lepšík M, Peclinovská L, Majer P, Strisovsky K. EMBO J. 33 2408-2421 (2014)
  2. 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 61 329-340 (2016)
  3. A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization. Wolf EV, Zeißler A, Vosyka O, Zeiler E, Sieber S, Verhelst SH. PLoS ONE 8 e72307 (2013)