ArticleACS central science2018
REDOR NMR Reveals Multiple Conformers for a Protein Kinase C Ligand in a Membrane Environment.
Article in ACS central science, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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Who cites it
24 citing papers in PubMed, 36 citations in OpenAlex.
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- Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity.Natural products and bioprospecting · 2025Article
- Synthesis and preclinical evaluation of tigilanol tiglate analogs as latency-reversing agents for the eradication of HIV.Science advances · 2025Article
- Very broad distribution of β sheet registries of the HIV gp41 fusion peptide supports mutational robustness for fusion and infection.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Topological Heterogeneity of Protein Kinase C Modulators in Human T-Cells Resolved with In-Cell Dynamic Nuclear Polarization NMR Spectroscopy.Journal of the American Chemical Society · 2024Article
- Tigliane Diterpenoids.Progress in the chemistry of organic natural products · 2024Review
- Three Decades of REDOR in Protein Science: A Solid-State NMR Technique for Distance Measurement and Spectral Editing.International journal of molecular sciences · 2023Review
- Expanding the Paradigm of Structure-Based Drug Design: Molecular Dynamics Simulations Support the Development of New Pyridine-Based Protein Kinase C-Targeted Agonists.Journal of medicinal chemistry · 2023Article
- From Angstroms to Nanometers: Measuring Interatomic Distances by Solid-State NMR.Chemical reviews · 2022Review
- Binding Sites of a Positron Emission Tomography Imaging Agent in Alzheimer's β-Amyloid Fibrils Studied UsingJournal of the American Chemical Society · 2022Article
- Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation.Cell chemical biology · 2021Article
- Structural insights into C1-ligand interactions: Filling the gaps by in silico methods.Advances in biological regulation · 2021Review
- Solid-state NMR spectroscopy.Nature reviews. Methods primers · 2021Article
- Function-Oriented Synthesis: Design, Synthesis, and Evaluation of Highly Simplified Bryostatin Analogues.The Journal of organic chemistry · 2020Article
- In Situ Detection of Endogenous HIV Activation by Dynamic Nuclear Polarization NMR and Flow Cytometry.International journal of molecular sciences · 2020Article
- Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.Nature communications · 2020Article
- Fast electron paramagnetic resonance magic angle spinning simulations using analytical powder averaging techniques.The Journal of chemical physics · 2019Article
- High-Sensitivity Detection of NanometerThe journal of physical chemistry. B · 2019Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Bryostatin 1 (henceforth bryostatin) is in clinical trials for the treatment of Alzheimer's disease and for HIV/AIDS eradication. It is also a preclinical lead for cancer immunotherapy and other therapeutic indications. Yet nothing is known about the conformation of bryostatin bound to its protein kinase C (PKC) target in a membrane microenvironment. As a result, efforts to design more efficacious, better tolerated, or more synthetically accessible ligands have been limited to structures that do not include PKC or membrane effects known to influence PKC-ligand binding. This problem extends more generally to many membrane-associated proteins in the human proteome. Here, we use rotational-echo double-resonance (REDOR) solid-state NMR to determine the conformations of PKC modulators bound to the PKCδ-C1b domain in the presence of phospholipid vesicles. The conformationally limited PKC modulator phorbol diacetate (PDAc) is used as an initial test substrate. While unanticipated partitioning of PDAc between an immobilized protein-bound state and a mobile state in the phospholipid assembly was observed, a single conformation in the bound state was identified. In striking contrast, a bryostatin analogue (bryolog) was found to exist exclusively in a protein-bound state, but adopts a distribution of conformations as defined by three independent distance measurements. The detection of multiple PKCδ-C1b-bound bryolog conformers in a functionally relevant phospholipid complex reveals the inherent dynamic nature of cellular systems that is not captured with single-conformation static structures. These results indicate that binding, selectivity, and function of PKC modulators, as well as the design of new modulators, are best addressed using a dynamic multistate model, an analysis potentially applicable to other membrane-associated proteins.
Identifiers
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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.