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[NMR paper] Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions.
Jul 08, 2020 - 5:24 PM - by nmrlearner
nmrlearner's Avatar Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions.

Related Articles Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions.

Molecules. 2020 Jul 01;25(13):

Authors: Musielak B, Janczyk W, Rodriguez I, Plewka J, Sala D, Magiera-Mularz K, Holak T

Abstract
Screening for small-molecule fragments that can lead to potent inhibitors of protein-protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low ?M-mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak ?M-mM ligand-protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex's protein that is not targeted by the inhibitor, we lower the effective affinity of the complex, allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.


PMID: 32630327 [PubMed - in process]



... [Read More]
0 Replies | 1 Views
[NMR paper] In Situ Detection of Endogenous HIV Activation by Dynamic Nuclear Polarization NMR and Flow Cytometry.
Jul 08, 2020 - 5:24 PM - by nmrlearner
nmrlearner's Avatar In Situ Detection of Endogenous HIV Activation by Dynamic Nuclear Polarization NMR and Flow Cytometry.

Related Articles In Situ Detection of Endogenous HIV Activation by Dynamic Nuclear Polarization NMR and Flow Cytometry.

Int J Mol Sci. 2020 Jun 30;21(13):

Authors: Overall SA, Price LE, Albert BJ, Gao C, Alaniva N, Judge PT, Sesti EL, Wender PA, Kyei GB, Barnes AB

Abstract
We demonstrate for the first time in-cell dynamic nuclear polarization (DNP) in conjunction with flow cytometry sorting to address the cellular heterogeneity of in-cell samples. Utilizing a green fluorescent protein (GFP) reporter of HIV reactivation, we correlate increased 15N resonance intensity with cytokine-driven HIV reactivation in a human cell line model of HIV latency. As few as 10% GFP+ cells could be detected by DNP nuclear magnetic resonance (NMR). The inclusion of flow cytometric sorting of GFP+ cells prior to analysis by DNP-NMR further boosted signal detection through increased cellular homogeneity with respect to GFP expression. As few as 3.6 million 15N-labeled GFP+ cells could be readily detected with DNP-NMR. Importantly, cell sorting allowed for the comparison of cytokine-treated GFP+ and GFP- cells in a batch-consistent way. This provides an avenue for normalizing NMR spectral contributions from background cellular processes following treatment with cellular modulators. We also demonstrate the... [Read More]
0 Replies | 1 Views
[NMR paper] How does the mood stabilizer lithium bind ATP, the energy Earnings of the cell: Insights from solid-state NMR.
Jul 08, 2020 - 5:24 PM - by nmrlearner
nmrlearner's Avatar How does the mood stabilizer lithium bind ATP, the energy Earnings of the cell: Insights from solid-state NMR.

Related Articles How does the mood stabilizer lithium bind ATP, the energy Earnings of the cell: Insights from solid-state NMR.

Biochim Biophys Acta Gen Subj. 2020 01;1864(1):129456

Authors: Haimovich A, Goldbourt A

Abstract
BACKGROUND: Lithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known.
METHODS: Here we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach.
RESULTS: We determine that the coordination sphere of lithium includes, at a distance of 3.0(0.4) , three phosphates; the two... [Read More]
0 Replies | 1 Views
CcpNmr AnalysisScreen, a new software programme with dedicated automated analysis tools for fragment-based drug discovery by NMR
Jul 08, 2020 - 3:03 AM - by nmrlearner
nmrlearner's Avatar CcpNmr AnalysisScreen, a new software programme with dedicated automated analysis tools for fragment-based drug discovery by NMR

Abstract

Fragment-based drug discovery or FBDD is one of the main methods used by industry and academia for identifying drug-like candidates in early stages of drug discovery. NMR has a significant impact at any stage of the drug discovery process, from primary identification of small molecules to the elucidation of binding modes for guiding optimisations. The essence of NMR as an analytical tool, however, requires the processing and analysis of relatively large amounts of single data items, e.g. spectra, which can be daunting when managed manually. One bottleneck in FBDD by NMR is a lack of adequate and well-integrated resources for NMR data analysis that are freely available to the community. Thus, scientists typically resort to manually inspecting large datasets and relying predominantly on subjective interpretations. In this manuscript, we present CcpNmr AnalysisScreen, a software package that provides computational tools for automated analysis of FBDD data by NMR. We outline how the quality of collected spectra can be evaluated quickly, and how robust workflows can be optimised for reliable and rapid hit identification. With an intuitive graphical user interface and powerful algorithms, AnalysisScreen enables easy analysis of the large datasets needed in the early process of drug discovery by NMR.



Source: Journal of Biomolecular NMR
0 Replies | 6 Views
A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily - Science
Jul 08, 2020 - 3:03 AM - by nmrlearner
nmrlearner's Avatar A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily - Science

A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily Science Read here
0 Replies | 2 Views
The global protein crystallization and crystallography market is estimated to grow from USD 1.1 billion in 2020 to USD 1.7 billion by 2025, at a CAGR of 8.9% - Salamanca Press
Jul 06, 2020 - 10:57 PM - by nmrlearner
nmrlearner's Avatar The global protein crystallization and crystallography market is estimated to grow from USD 1.1 billion in 2020 to USD 1.7 billion by 2025, at a CAGR of 8.9% - Salamanca Press

The global protein crystallization and crystallography market is estimated to grow from USD 1.1 billion in 2020 to USD 1.7 billion by 2025, at a CAGR of 8.9% Salamanca Press Read here
0 Replies | 4 Views
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