ArticleEuropean biophysics journal : EBJ2006
X-ray, neutron and NMR studies of the catalytic mechanism of aspartic proteinases.
Article in European biophysics journal : EBJ, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds.Biochemistry · 2026Article
- Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds.bioRxiv : the preprint server for biology · 2025Article
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Structural and time-resolved mechanistic investigations of protein hydrolysis by the acidic proline-specific endoprotease from Aspergillus niger.Protein science : a publication of the Protein Society · 2024Article
- Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.Communications biology · 2023Article
- Discovery of new Schistosoma mansoni aspartyl protease inhibitors by structure-based virtual screening.Memorias do Instituto Oswaldo Cruz · 2023Article
- Protein-Templated Hit Identification through an Ugi Four-Component Reaction*.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Biochemical characterization of two new3 Biotech · 2020Article
- Article
- Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.ChemMedChem · 2018Article
- Short Carboxylic Acid-Carboxylate Hydrogen Bonds Can Have Fully Localized Protons.Biochemistry · 2017Article
- Dynamic and Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease.Journal of the American Chemical Society · 2016Article
- Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2016Article
- Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.Angewandte Chemie (International ed. in English) · 2016Article
- Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.International journal of molecular sciences · 2015Article
- Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β -Secretase.Scientifica · 2014Review
- Aspartic peptidases of human pathogenic trypanosomatids: perspectives and trends for chemotherapy.Current medicinal chemistry · 2013Review
- HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos.World journal of biological chemistry · 2010Article
- A preliminary neutron crystallographic study of an A-DNA crystal.Acta crystallographica. Section F, Structural biology and crystallization communications · 2009Article
- Neutron crystallography: opportunities, challenges, and limitations.Current opinion in structural biology · 2008Review
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Authors and funding
7 authors.
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Abstract
Current proposals for the catalytic mechanism of aspartic proteinases are largely based on X-ray structures of bound oligopeptide inhibitors possessing non-hydrolysable analogues of the scissile peptide bond. Until recent years, the positions of protons on the catalytic aspartates and the ligand in these complexes had not been determined with certainty due to the inadequate resolution of these analyses. There has been much interest in locating the catalytic protons at the active site of aspartic proteinases since this has major implications for detailed understanding of the mechanism of action and the design of improved transition state mimics for therapeutic applications. In this review we discuss the results of studies which have shed light on the locations of protons at the catalytic centre. The first direct determination of the proton positions stemmed from neutron diffraction data collected from crystals of the fungal aspartic proteinase endothiapepsin bound to a transition state analogue (H261). The neutron structure of the complex at a resolution of 2.1 A provided evidence that Asp 215 is protonated and that Asp 32 is the negatively charged residue in the transition state complex. Atomic resolution X-ray studies of inhibitor complexes have corroborated this finding. A similar study of the native enzyme established that it, unexpectedly, has a dipeptide bound at the catalytic site which is consistent with classical reports of inhibition by short peptides and the ability of pepsins to catalyse transpeptidation reactions. Studies by NMR have confirmed the findings of low-barrier and single-well hydrogen bonds in the complexes with transition state analogues.
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