ArticleScience advances2020
Targeting the cryptic sites: NMR-based strategy to improve protein druggability by controlling the conformational equilibrium.
Article in Science advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- DNA-Induced Entropic Gain Triggers an Allosteric Switch for Biomolecular Condensation of Heat Shock Transcription Factor 1.Angewandte Chemie (International ed. in English) · 2026Article
- Allosteric network of dynamic coupling within BAP1-UCH revealed by methyl NMR.Nature communications · 2026Article
- HBV HBx protein masks epigenetic reader Spindlin1 via an inter-molecular zinc finger to subvert transcriptional control.Nature communications · 2026Article
- CryptoBank: A resource for the identification and prediction of cryptic sites in proteins.Science advances · 2026Article
- Structure-based Discovery of a Non-competitive FTO Inhibitor Bound to a Cryptic Site at the Domain Interface.Journal of molecular biology · 2026Article
- Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism.Nature communications · 2025Article
- Evaluation of Small-Molecule Binding Site Prediction Methods on Membrane-Embedded Protein Interfaces.Journal of chemical information and modeling · 2025Article
- Which cryptic sites are feasible drug targets?Drug discovery today · 2024Review
- Molecular mechanism of phosphopeptide neoantigen immunogenicity.Nature communications · 2023Article
- Mutual induced-fit mechanism drives binding between intrinsically disordered Bim and cryptic binding site of Bcl-xL.Communications biology · 2023Article
- Prediction of protein-ligand binding affinity with deep learning.Computational and structural biotechnology journal · 2023Review
- Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70.Molecules (Basel, Switzerland) · 2022Article
- Systematic Approach to Find the Global Minimum of Relaxation Dispersion Data for Protein-Induced B-Z Transition of DNA.International journal of molecular sciences · 2021Article
- Single-molecule analysis of interaction between p53TAD and MDM2 using aerolysin nanopores.Chemical science · 2021Article
- Cryptic-site binding mechanism of medium-sized Bcl-xL inhibiting compounds elucidated by McMD-based dynamic docking simulations.Scientific reports · 2021Article
- Druggable Transient Pockets in Protein Kinases.Molecules (Basel, Switzerland) · 2021Review
- Drugging Fuzzy Complexes in Transcription.Frontiers in molecular biosciences · 2021Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cryptic ligand binding sites, which are not evident in the unligated structures, are beneficial in tackling with difficult but attractive drug targets, such as protein-protein interactions (PPIs). However, cryptic sites have thus far not been rationally pursued in the early stages of drug development. Here, we demonstrated by nuclear magnetic resonance that the cryptic site in Bcl-xL exists in a conformational equilibrium between the open and closed conformations under the unligated condition. While the fraction of the open conformation in the unligated wild-type Bcl-xL is estimated to be low, F143W mutation that is distal from the ligand binding site can substantially elevate the population. The F143W mutant showed a higher hit rate in a phage-display peptide screening, and the hit peptide bound to the cryptic site of the wild-type Bcl-xL. Therefore, by controlling the conformational equilibrium in the cryptic site, the opportunity to identify a PPI inhibitor could be improved.
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Registered trials
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.