ArticleAngewandte Chemie (International ed. in English)2020
The Active Site of a Prototypical "Rigid" Drug Target is Marked by Extensive Conformational Dynamics.
Article in Angewandte Chemie (International ed. in English), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Lipid Pocket Binders Impose Allosteric Changes of Protein Dynamics Around the Active Site of the Protein Kinase p38α.Angewandte Chemie (International ed. in English) · 2026Article
- Epigenetic CpG duplex marks probed by an evolved DNA reader via a well-tempered conformational plasticity.Nucleic acids research · 2023Article
- Spatially Resolved Hydration Thermodynamics in Biomolecular Systems.The journal of physical chemistry. B · 2022Review
- Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR.Nature communications · 2022Article
- Switching the Inhibitor-Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII.ChemistryOpen · 2021Article
- The Active Site of a Prototypical "Rigid" Drug Target is Marked by Extensive Conformational Dynamics.Angewandte Chemie (International ed. in English) · 2020Article
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Authors and funding
6 authors.
Funding
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Abstract
Drug discovery, in particular optimization of candidates using medicinal chemistry, is generally guided by structural biology. However, for optimizing binding kinetics, relevant for efficacy and off-target effects, information on protein motion is important. Herein, we demonstrate for the prototypical textbook example of an allegedly "rigid protein" that substantial active-site dynamics have generally remained unrecognized, despite thousands of medicinal-chemistry studies on this model over decades. Comparing cryogenic X-ray structures, solid-state NMR on micro-crystalline protein at room temperature, and solution NMR structure and dynamics, supported by MD simulations, we show that under physiologically relevant conditions the pocket is in fact shaped by pronounced open/close conformational-exchange dynamics. The study, which is of general significance for pharmacological research, evinces a generic pitfall in drug discovery routines.
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Registered trials
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