ArticleJournal of chemical information and modeling2024
Mapping Protein Conformational Landscapes from Crystallographic Drug Fragment Screens.
Article in Journal of chemical information and modeling, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Representative Conformational Sampling for Chiroptical Analysis of the Flexible Dopamine Agonist Rotigotine.Pharmaceuticals (Basel, Switzerland) · 2026Article
- In Silico Isomerization Produces Apt Negative Data for VHTS Validation.Journal of chemical information and modeling · 2026Article
- Statistical crystallography reveals an allosteric network in SARS-CoV-2 MCommunications biology · 2026Article
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
- Crystallographic Ensembles Reveal the Structural Basis of Binding Entropy in SARS-CoV2 Macrodomain.bioRxiv : the preprint server for biology · 2025Article
- Article
- Orchestrating function: Concerted dynamics, allostery, and catalysis in protein tyrosine phosphatases.Current opinion in structural biology · 2025Review
- Mapping allosteric rewiring in related protein structures from collections of crystallographic multiconformer models.bioRxiv : the preprint server for biology · 2025Article
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3 authors.
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Abstract
Proteins are dynamic macromolecules. Knowledge of a protein's thermally accessible conformations is critical to determining important transitions and designing therapeutics. Accessible conformations are highly constrained by a protein's structure such that concerted structural changes due to external perturbations likely track intrinsic conformational transitions. These transitions can be thought of as paths through a conformational landscape. Crystallographic drug fragment screens are high-throughput perturbation experiments, in which thousands of crystals of a drug target are soaked with small-molecule drug precursors (fragments) and examined for fragment binding, mapping potential drug binding sites on the target protein. Here, we describe an open-source Python package, COnformational LAndscape Visualization (COLAV), to infer conformational landscapes from such large-scale crystallographic perturbation studies. We apply COLAV to drug fragment screens of two medically important systems: protein tyrosine phosphatase 1B (PTP1B), which regulates insulin signaling, and the SARS CoV-2 Main Protease (MPro). With enough fragment-bound structures, we find that such drug screens enable detailed mapping of proteins' conformational landscapes.
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