ArticleProceedings of the National Academy of Sciences of the United States of America2015
Detection of secondary binding sites in proteins using fragment screening.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 125 citations in OpenAlex.
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- CryptoBank: A resource for the identification and prediction of cryptic sites in proteins.Science advances · 2026Article
- Decrypting cryptic pockets with physics-based simulations and artificial intelligence.Current opinion in structural biology · 2026Review
- Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Discovering Uncharted Binding Pockets on E3 Ligases Leads to the Identification of FBW7 Allosteric Modulators.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The identification of functional regions of MEK1 using CRISPR tiling screens.Communications biology · 2025Article
- Macromolecular crystallography from an industrial perspective - the impact of synchrotron radiation on structure-based drug discovery.Journal of synchrotron radiation · 2025Article
- Targeting cyclin-dependent kinase 2 (CDK2) interactions with cyclins and Speedy 1 (Spy1) for cancer and male contraception.Future medicinal chemistry · 2025Review
- Structural Chemistry of Helicase Inhibition.Journal of medicinal chemistry · 2025Review
- Fragment Screening Identifies Novel Allosteric Binders and Binding Sites in the VHR (ACS omega · 2025Article
- Structural Biology for Target Identification and Validation.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Recent computational advances in the identification of cryptic binding sites for drug discovery.Bioinformatics advances · 2025Review
- Structure of the SMYD2-PARP1 Complex Reveals Both Productive and Allosteric Modes of Peptide Binding.bioRxiv : the preprint server for biology · 2024Article
- Article
- Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function.Nature communications · 2024Article
- Which cryptic sites are feasible drug targets?Drug discovery today · 2024Review
- The "Doorstop Pocket" In Thioredoxin Reductases─An Unexpected Druggable Regulator of the Catalytic Machinery.Journal of medicinal chemistry · 2024Review
- Secondary Sites of the C-type Lectin-Like Fold.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.
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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.