ArticleThe Journal of biological chemistry2012
Catalytic mechanism of rhomboid protease GlpG probed by 3,4-dichloroisocoumarin and diisopropyl fluorophosphonate.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 53 citations in OpenAlex.
- Rhomboid Proteases in Plasmodium spp. : Biology, Functional Roles, and Therapeutic Potential.Acta parasitologica · 2026Review
- Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.Chembiochem : a European journal of chemical biology · 2025Review
- Article
- A Protocol to Depict the Proteolytic Processes Using a Combination of Metal-Organic Materials (MOMs), Electron Paramagnetic Resonance (EPR), and Mass Spectrometry (MS).Bio-protocol · 2024Article
- Effect of Environmental Factors on the Catalytic Activity of Intramembrane Serine Protease.Journal of the American Chemical Society · 2022Article
- Article
- Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors.RSC advances · 2021Article
- Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Bacterial rhomboid proteases mediate quality control of orphan membrane proteins.The EMBO journal · 2020Article
- The rhomboid protease GlpG has weak interaction energies in its active site hydrogen bond network.The Journal of general physiology · 2019Article
- Discovery and Biological Evaluation of Potent and Selective N-Methylene Saccharin-Derived Inhibitors for Rhomboid Intramembrane Proteases.Biochemistry · 2017Article
- Alternative Processing of the Amyloid Precursor Protein Family by Rhomboid Protease RHBDL4.The Journal of biological chemistry · 2016Article
- Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis.Molecular cell · 2016Article
- Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.The Journal of membrane biology · 2015Review
- Influence of hydrophobic mismatch on the catalytic activity of Escherichia coli GlpG rhomboid protease.Protein science : a publication of the Protein Society · 2015Article
- Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures.The EMBO journal · 2014Article
- Allosteric regulation of rhomboid intramembrane proteolysis.The EMBO journal · 2014Article
- Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity.Cell · 2013Article
- Biochemical and structural insights into intramembrane metalloprotease mechanisms.Biochimica et biophysica acta · 2013Review
- Residues in conserved loops of intramembrane metalloprotease SpoIVFB interact with residues near the cleavage site in pro-σK.Journal of bacteriology · 2013Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Rhomboid proteases have many important biological functions. Unlike soluble serine proteases such as chymotrypsin, the active site of rhomboid protease, which contains a Ser-His catalytic dyad, is submerged in the membrane and surrounded by membrane-spanning helices. Previous crystallographic analyses of GlpG, a bacterial rhomboid protease, and its complex with isocoumarin have provided insights into the mechanism of the membrane protease. Here, we studied the interaction of GlpG with 3,4-dichloroisocoumarin and diisopropyl fluorophosphonate, both mechanism-based inhibitors for the serine protease, and describe the crystal structure of the covalent adduct between GlpG and diisopropyl fluorophosphonate, which mimics the oxyanion-containing tetrahedral intermediate of the hydrolytic reaction. The crystal structure confirms that the oxyanion is stabilized by the main chain amide of Ser-201 and by the side chains of His-150 and Asn-154. The phosphorylation of the catalytic Ser-201 weakens its interaction with His-254, causing the catalytic histidine to rotate away from the serine. The rotation of His-254 is accompanied by further rearrangement of the side chains of Tyr-205 and Trp-236 within the substrate-binding groove. The formation of the tetrahedral adduct is also accompanied by opening of the L5 cap and movement of transmembrane helix S5 toward S6 in a direction different from that predicted by the lateral gating model. Combining the new structural data with those on the isocoumarin complex sheds further light on the plasticity of the active site of rhomboid membrane protease.
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