ArticleeLife2023
Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 71 citations in OpenAlex.
- Perspectives for pharmaceutical screening at XFEL sources using the example of Lassa virus endonuclease.Acta crystallographica. Section D, Structural biology · 2026Article
- Structural insights into urocanate reductase using room-temperature X-ray crystallography.Acta crystallographica. Section D, Structural biology · 2026Article
- An integrated experimental and computational pipeline for crystallographic fragment screening of membrane protein in the lipid cubic phase.Communications chemistry · 2026Article
- Structural basis for substrate-dependent allostery in oxygen activation by a cytochrome P450 enzyme revealed by analysis at different temperatures.Chemical science · 2026Article
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
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- Towards patient-relevant structures: reviewing body-temperature biological macromolecules and their ligands for pharmaceutical applications.Acta crystallographica. Section D, Structural biology · 2026Review
- False Friends in Fluorescence - Simple HPLC Evaluation of False Positive Fragment Hits in a DiFMUP Assay for Protein Tyrosine Phosphatase 1B.Drug design, development and therapy · 2026Article
- Sensitive detection of structural dynamics using a statistical framework for comparative crystallography.Science advances · 2025Article
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- Binding mode of Isoxazolyl Penicillins to a Class-A β-lactamase at ambient conditions.Communications chemistry · 2025Article
- Room-temperature X-ray fragment screening with serial crystallography.Nature communications · 2025Article
- Orchestrating function: Concerted dynamics, allostery, and catalysis in protein tyrosine phosphatases.Current opinion in structural biology · 2025Review
- Solvation Energetic Costs of Cognate Binding Site Formation.Journal of chemical information and modeling · 2025Article
- Macromolecular crystallography for mammalian body temperature in support of molecular biophysics methods.Biophysical reviews · 2025Review
- Probing the modulation of enzyme kinetics by multi-temperature, time-resolved serial crystallography.Nature communications · 2025Article
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- Advances in microfluidic mixers for time-resolved structural biology with X-rays.Biophysical reviews · 2025Review
- Enhanced intensity-based clustering of isomorphous multi-crystal data sets in the presence of subtle variations.Acta crystallographica. Section D, Structural biology · 2025Article
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Authors and funding
13 authors at 4 institutions in 4 countries.
Funding
Abstract
Much of our current understanding of how small-molecule ligands interact with proteins stems from X-ray crystal structures determined at cryogenic (cryo) temperature. For proteins alone, room-temperature (RT) crystallography can reveal previously hidden, biologically relevant alternate conformations. However, less is understood about how RT crystallography may impact the conformational landscapes of protein-ligand complexes. Previously, we showed that small-molecule fragments cluster in putative allosteric sites using a cryo crystallographic screen of the therapeutic target PTP1B (Keedy et al., 2018). Here, we have performed two RT crystallographic screens of PTP1B using many of the same fragments, representing the largest RT crystallographic screens of a diverse library of ligands to date, and enabling a direct interrogation of the effect of data collection temperature on protein-ligand interactions. We show that at RT, fewer ligands bind, and often more weakly - but with a variety of temperature-dependent differences, including unique binding poses, changes in solvation, new binding sites, and distinct protein allosteric conformational responses. Overall, this work suggests that the vast body of existing cryo-temperature protein-ligand structures may provide an incomplete picture, and highlights the potential of RT crystallography to help complete this picture by revealing distinct conformational modes of protein-ligand systems. Our results may inspire future use of RT crystallography to interrogate the roles of protein-ligand conformational ensembles in biological function.
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