ArticleBiophysical journal2020
Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.
Article in Biophysical journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
5 citing papers in PubMed.
- Aortic disease-linked mutations reveal unexpected convergent allosteric mechanisms of protein kinase G misregulation.Science advances · 2026Article
- Is There a Need for a More Precise Description of Biomolecule Interactions to Understand Cell Function?Current issues in molecular biology · 2022Review
- State-selective frustration as a key driver of allosteric pluripotency.Chemical science · 2021Article
- Adding Substituent Nonadditivity in Protein Allostery by NMR.Biophysical journal · 2020Article
- Allosteric inhibition explained through conformational ensembles sampling distinct "mixed" states.Computational and structural biotechnology journal · 2020Review
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6 authors.
Funding
Abstract
Quantifying chemical substituent contributions to ligand-binding free energies is challenging due to nonadditive effects. Protein allostery is a frequent cause of nonadditivity, but the underlying allosteric mechanisms often remain elusive. Here, we propose a general NMR-based approach to elucidate such mechanisms and we apply it to the HCN4 ion channel, whose cAMP-binding domain is an archetypal conformational switch. Using NMR, we show that nonadditivity arises not only from concerted conformational transitions, but also from conformer-specific effects, such as steric frustration. Our results explain how affinity-reducing functional groups may lead to affinity gains if combined. Surprisingly, our approach also reveals that nonadditivity depends markedly on the receptor conformation. It is negligible for the inhibited state but highly significant for the active state, opening new opportunities to tune potency and agonism of allosteric effectors.
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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.