ArticleProceedings of the National Academy of Sciences of the United States of America2021
Opening of a cryptic pocket in β-lactamase increases penicillinase activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Article
- Topological metrics as evolutionary and dynamical descriptors of conformational landscapes within protein families.PLoS computational biology · 2026Article
- Decrypting cryptic pockets with physics-based simulations and artificial intelligence.Current opinion in structural biology · 2026Review
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- Article
- Opening and closing of a cryptic pocket in VP35 toggles it between two different RNA-binding modes.eLife · 2025Article
- Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding.The journal of physical chemistry. B · 2025Article
- Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding.bioRxiv : the preprint server for biology · 2025Article
- Accounting for Fast vs Slow Exchange in Single Molecule FRET Experiments Reveals Hidden Conformational States.Journal of chemical theory and computation · 2024Article
- Accounting for fast vs slow exchange in single molecule FRET experiments reveals hidden conformational states.bioRxiv : the preprint server for biology · 2024Article
- SWISH-X, an Expanded Approach to Detect Cryptic Pockets in Proteins and at Protein-Protein Interfaces.Journal of chemical theory and computation · 2024Article
- Multilevel superposition for deciphering the conformational variability of protein ensembles.Briefings in bioinformatics · 2024Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β.Nature communications · 2023Article
- Loop dynamics and the evolution of enzyme activity.Nature reviews. Chemistry · 2023Review
- Folding@home: Achievements from over 20 years of citizen science herald the exascale era.Biophysical journal · 2023Review
- Accelerating Cryptic Pocket Discovery Using AlphaFold.Journal of chemical theory and computation · 2023Article
- Local Xenon-Protein Interaction Produces Global Conformational Change and Allosteric Inhibition in Lysozyme.Biochemistry · 2023Article
- Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.Protein science : a publication of the Protein Society · 2023Article
- Folding@home: achievements from over twenty years of citizen science herald the exascale era.ArXiv · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Understanding the functional role of protein-excited states has important implications in protein design and drug discovery. However, because these states are difficult to find and study, it is still unclear if excited states simply result from thermal fluctuations and generally detract from function or if these states can actually enhance protein function. To investigate this question, we consider excited states in β-lactamases and particularly a subset of states containing a cryptic pocket which forms under the Ω-loop. Given the known importance of the Ω-loop and the presence of this pocket in at least two homologs, we hypothesized that these excited states enhance enzyme activity. Using thiol-labeling assays to probe Ω-loop pocket dynamics and kinetic assays to probe activity, we find that while this pocket is not completely conserved across β-lactamase homologs, those with the Ω-loop pocket have a higher activity against the substrate benzylpenicillin. We also find that this is true for TEM β-lactamase variants with greater open Ω-loop pocket populations. We further investigate the open population using a combination of NMR chemical exchange saturation transfer experiments and molecular dynamics simulations. To test our understanding of the Ω-loop pocket's functional role, we designed mutations to enhance/suppress pocket opening and observed that benzylpenicillin activity is proportional to the probability of pocket opening in our designed variants. The work described here suggests that excited states containing cryptic pockets can be advantageous for function and may be favored by natural selection, increasing the potential utility of such cryptic pockets as drug targets.
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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.