NMR and Computational Methods in the Structural and Dynamic Characterization of Ligand-Receptor Interactions

Ghitti, Michela; Musco, Giovanna; Spitaleri, Andrea

doi:10.1007/978-3-319-02970-2_12

Cited by 10 publications

(6 citation statements)

References 146 publications

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“…Protein-ligand interactions can be investigated by examining the increase in the transverse relaxation rate of the ligand NMR signal. The transverse relaxation rate is accelerated by the decreased rotational diffusion rate and increased rotational correlation time due to protein-ligand binding [ 19 ]. In T 2 - and T 1ρ -filter [ 20 , 21 , 22 ] experiments ( Figure 2 a), protein-ligand binding was detected by the decrease in resonance intensity of the ligand NMR signals.…”

Section: Nmr Spectroscopy Aimed At Drug Discovery-ligand-based Andmentioning

confidence: 99%

Current NMR Techniques for Structure-Based Drug Discovery

et al. 2018

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A variety of nuclear magnetic resonance (NMR) applications have been developed for structure-based drug discovery (SBDD). NMR provides many advantages over other methods, such as the ability to directly observe chemical compounds and target biomolecules, and to be used for ligand-based and protein-based approaches. NMR can also provide important information about the interactions in a protein-ligand complex, such as structure, dynamics, and affinity, even when the interaction is too weak to be detected by ELISA or fluorescence resonance energy transfer (FRET)-based high-throughput screening (HTS) or to be crystalized. In this study, we reviewed current NMR techniques. We focused on recent progress in NMR measurement and sample preparation techniques that have expanded the potential of NMR-based SBDD, such as fluorine NMR (19F-NMR) screening, structure modeling of weak complexes, and site-specific isotope labeling of challenging targets.

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Section: Nmr Spectroscopy Aimed At Drug Discovery-ligand-based Andmentioning

confidence: 99%

Current NMR Techniques for Structure-Based Drug Discovery

et al. 2018

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“…Combination of methods like nuclear magnetic resonance (NMR) spectroscopy, molecular dynamic simulations and molecular docking, biophysical methods like isothermal titration calorimetry (ITC) and fluorescence spectroscopy allows deep characterization of the interaction processes taking into account dynamic conformational variations [126][127][128].…”

Section: Conformational Selection In Structural Biology Relevance Anmentioning

confidence: 99%

1H, 13C, and 15N resonance assignments of CW domain of the N-methyltransferase ASHH2 free and bound to the mono-, di- and tri-methylated histone H3 tail peptides

et al. 2018

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The ASHH2 CW domain is responsible for recognizing the methylation state at lysine 4 of histone 3 N-terminal tails and implicated in the recruitment of the ASHH2 methyltransferase enzyme correctly to the histones. The ASHH2 CW domain binds H3 lysine motifs that can be either mono-, di-, or tri-methylated [ARTK(meX)QTAR, where X denotes the number of methylations], but binds strongest to monomethylated instances (K values reported in the range of 1 µm to 500 nM). Hoppmann et al. published the uncomplexed NMR structure of an ASHH2 CW domain in 2011. Here we document the assignment of a shortened ASHH2 CW construct, CW42, with similar binding affinity and better expression yields than the one used to solve the uncomplexed structure. We also perform H-N HSQC-monitored titrations that document at which protein-peptide ratios the complex is saturated. Backbone resonance assignments are presented for this shortened ASHH2 CW domain alone and bound to an H3 histone tail mimicking peptide monomethylated on lysine 4 (ARTK(me1)QTAR). Likewise, the assignment was also performed for the protein in complex with the dimethylated (ARTK(me2)QTAR) and trimethylated (ARTK(me3)QTAR) peptide. Overall, these two latter situations displayed a similar perturbation of shifts as the mono-methylated instance. In the case of the monomethylated histone tail mimic, side-chain assignment of CW42 in this complex was performed and reported in addition to backbone assignment, in preparation of a future solution structure determination and dynamics characterization of the CW42-ARTK(me1)QTAR complex.

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“…In fact, the full topology of the molecule has a profound impact on its biological and pharmacological properties. Nowadays several methods, mainly relying on NMR and computational approaches have provided a reliable access to the configurational assignment of even complex and flexible molecules [54]. In particular, J-based configuration analysis is a powerful yet simple technique for determining stereochemistry and conformation of a molecule [55].…”

Section: Sustainable Biotechnological Productionmentioning

confidence: 99%

Exploring Marine Resources for Bioactive Compounds

et al. 2014

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Biodiversity in the seas is only partly explored, although marine organisms are excellent sources for many industrial products. Through close co-operation between industrial and academic partners, it is possible to successfully collect, isolate and classify marine organisms, such as bacteria, fungi, micro- and macroalgae, cyanobacteria, and marine invertebrates from the oceans and seas globally. Extracts and purified compounds of these organisms can be studied for several therapeutically and industrially significant biological activities, including anticancer, anti-inflammatory, antiviral, antibacterial, and anticoagulant activities by applying a wide variety of screening tools, as well as for ion channel/receptor modulation and plant growth regulation. Chromatographic isolation of bioactive compounds will be followed by structural determination. Sustainable cultivation methods for promising organisms and biotechnological processes for selected compounds can be developed, as well as biosensors for monitoring the target compounds. The (semi)synthetic modification of marine-based bioactive compounds produces their new derivatives, structural analogs and mimetics that could serve as hit or lead compounds and be used to expand compound libraries based on marine natural products. The research innovations can be targeted for industrial product development in order to improve the growth and productivity of marine biotechnology. Marine research aims at a better understanding of environmentally conscious sourcing of marine biotechnology products and increased public awareness of marine biodiversity. Marine research is expected to offer novel marine-based lead compounds for industries and strengthen their product portfolios related to pharmaceutical, nutraceutical, cosmetic, agrochemical, food processing, material and biosensor applications.

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NMR and Computational Methods in the Structural and Dynamic Characterization of Ligand-Receptor Interactions

Cited by 10 publications

References 146 publications

Current NMR Techniques for Structure-Based Drug Discovery

Current NMR Techniques for Structure-Based Drug Discovery

1H, 13C, and 15N resonance assignments of CW domain of the N-methyltransferase ASHH2 free and bound to the mono-, di- and tri-methylated histone H3 tail peptides

Exploring Marine Resources for Bioactive Compounds

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