ArticleStructure (London, England : 1993)2024
An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.
Article in Structure (London, England : 1993), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- From possibility to precision in macromolecular ensemble prediction.Nature methods · 2026Review
- Loop dynamics, allostery, and function in protein tyrosine phosphatases: insights from molecular simulations.Biochemical Society transactions · 2026Review
- Article
- Molecular dynamics simulation in traditional Chinese medicine research: from molecular mechanisms to multiscale validation.Frontiers in chemistry · 2026Review
- Article
- Orchestrating function: Concerted dynamics, allostery, and catalysis in protein tyrosine phosphatases.Current opinion in structural biology · 2025Review
- An experimental proxy of water displaceability for ligand discovery.Nature methods · 2025Article
- Article
- Mapping allosteric rewiring in related protein structures from collections of crystallographic multiconformer models.bioRxiv : the preprint server for biology · 2025Article
- Where and how to house big data on small fragments.Nature communications · 2025Review
- Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments.bioRxiv : the preprint server for biology · 2025Article
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Abstract
Due to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an "undruggable" therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) "hidden" ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.
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