ArticleJournal of the American Chemical Society2008
The catalytic mechanism of an aspartic proteinase explored with neutron and X-ray diffraction.
Article in Journal of the American Chemical Society, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 122 citations in OpenAlex.
- Deconstruction of Aspartic Protease Inhibitors Enables Fragment-Based Discovery of Plasmepsin V Inhibitors.ChemMedChem · 2026Article
- The Adaptable Binding Cleft of RmuAP1, a Pepsin-like Peptidase fromBiomolecules · 2025Article
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 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
- Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies.International journal of molecular sciences · 2021Review
- On the Case of the Misplaced Hydrogens.Chembiochem : a European journal of chemical biology · 2021Review
- Low barrier hydrogen bonds in protein structure and function.Biochimica et biophysica acta. Proteins and proteomics · 2021Review
- Protein-Templated Hit Identification through an Ugi Four-Component Reaction*.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Article
- AnACS catalysis · 2019Article
- Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.ChemMedChem · 2018Article
- Improving the accuracy and resolution of neutron crystallographic data by three-dimensional profile fitting of Bragg peaks in reciprocal space.Acta crystallographica. Section D, Structural biology · 2018Article
- Short Carboxylic Acid-Carboxylate Hydrogen Bonds Can Have Fully Localized Protons.Biochemistry · 2017Article
- Review
- 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
- XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement.Acta crystallographica. Section D, Structural biology · 2016Article
- Determination of the protonation state of the Asp dyad: conventional molecular dynamics versus thermodynamic integration.Journal of molecular modeling · 2016Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
Hydrogen atoms play key roles in enzyme mechanism, but as this study shows, even high-quality X-ray data to a resolution of 1 A cannot directly visualize them. Neutron diffraction, however, can locate deuterium atoms even at resolutions around 2 A. Both neutron and X-ray diffraction data have been used to investigate the transition state of the aspartic proteinase endothiapepsin. The different techniques reveal a different part of the story, revealing the clearest picture yet of the catalytic mechanism by which the enzyme operates. Room temperature neutron and X-ray diffraction data were used in a newly developed joint refinement software package to visualize deuterium atoms within the active site of the enzyme when a gem-diol transition state analogue inhibitor is bound at the active site. These data were also used to estimate their individual occupancy, while analysis of the differences between the bond lengths of the catalytic aspartates was performed using atomic resolution X-ray data. The two methods are in agreement on the protonation state of the active site with a transition state analogue inhibitor bound confirming the catalytic mechanism at which the enzyme operates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.