Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

Shaw, Daniel J.; Waters, Lorna C.; Strong, Sarah L.; Schulze, Monika-Sarah E. D.; Greetham, Gregory M.; Towrie, Michael; Parker, Anthony W.; Prosser, Christine E.; Henry, Alistair J.; Lawson, Alastair D. G.; Carr, Mark D.; Taylor, Richard J. K.; Hunt, Neil T.; Muskett, Frederick W.

doi:10.1039/d3sc00728f

Cited by 3 publications

(3 citation statements)

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“…In this respect, demonstrating complementarity of IR tools with established methods will be important in disseminating the abilities that time resolved IR can now confer. Recent examples including combining 2D-IR and NMR for multiscale studies of dynamics of relevance to cytokine mechanisms 141 and linking time resolved IR with fs-X-ray crystallography data 88 have shown the potential reach and value of such approaches while it is encouraging to see advanced IR spectroscopy studies increasingly contributing to broader-based studies and supplementing research chiefly based in other disciplines such as chemical biology. 94,96,142 The field should embrace such opportunities as they bring new challenges which ultimately drive technique development, but also broaden the user base for ultrafast IR capability which will accelerate integration of the methods within the biomolecular research community.…”

Section: Discussionmentioning

confidence: 99%

Biomolecular infrared spectroscopy: making time for dynamics

Hunt

2024

Chem. Sci.

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Section: Discussionmentioning

confidence: 99%

Biomolecular infrared spectroscopy: making time for dynamics

Hunt

2024

Chem. Sci.

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“…Changes to the amide I band of a protein upon drug binding contain information relating to how the secondary structure and local dynamics are modified by the interaction. Applications of 2D-IR amide I spectroscopy in D 2 O have demonstrated significant drug-induced changes, which correlate with function of the drug molecule. , These effects were often associated with alterations in the dynamics of the protein rather than large-scale secondary structure changes, and thus, their detection relies on the sensitivity of 2D-IR to factors such as transition dipole moments or anharmonicities, which evade IR absorption measurements. , Differences in the H-bonding ability of H 2 O and D 2 O mean that H/D exchange may affect the balance of competitive solvation of the drug molecule and protein binding site, so measurements in the native solvent will be important while also removing the practical need to exchange buffer solutions or express proteins in deuterated media.…”

Section: Protein–drug Bindingmentioning

confidence: 99%

“…Applications of 2D-IR amide I spectroscopy in D 2 O have demonstrated significant drug-induced changes, which correlate with function of the drug molecule. 19 , 48 These effects were often associated with alterations in the dynamics of the protein rather than large-scale secondary structure changes, and thus, their detection relies on the sensitivity of 2D-IR to factors such as transition dipole moments or anharmonicities, which evade IR absorption measurements. 19 , 48 Differences in the H-bonding ability of H 2 O and D 2 O mean that H/D exchange may affect the balance of competitive solvation of the drug molecule and protein binding site, so measurements in the native solvent will be important 49 while also removing the practical need to exchange buffer solutions or express proteins in deuterated media.…”

Section: Protein–drug Bindingmentioning

confidence: 99%

Using 2D-IR Spectroscopy to Measure the Structure, Dynamics, and Intermolecular Interactions of Proteins in H₂O

Hunt

2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Infrared (IR) spectroscopy probes molecular structure at the level of the chemical bond or functional group. In the case of proteins, the most informative band in the IR spectrum is the amide I band, which arises predominantly from the C�O stretching vibration of the peptide link. The folding of proteins into secondary and tertiary structures leads to vibrational coupling between peptide units, generating specific amide I spectral signatures that provide a fingerprint of the macromolecular conformation. Ultrafast two-dimensional IR (2D-IR) spectroscopy allows the amide I band of a protein to be spread over a second frequency dimension in a way that mirrors 2D-NMR methods. This means that amide I 2D-IR spectroscopy produces a spectral map that is exquisitely sensitive to protein structure and dynamics and so provides detailed insights that cannot be matched by IR absorption spectroscopy. As a result, 2D-IR spectroscopy has emerged as a powerful tool for probing protein structure and dynamics over a broad range of time and length scales in the solution phase at room temperature. However, the protein amide I band coincides with an IR absorption from the bending vibration of water (δ HOH ), the natural biological solvent. To circumvent this problem, protein IR studies are routinely performed in D 2 O solutions because H/D substitution shifts the solvent bending mode (δ DOD ) to a lower frequency, revealing the amide I band. While effective, this method raises fundamental questions regarding the impact of the change in solvent mass on the structural or solvation dynamics of the protein and the removal of the energetic resonance between solvent and solute.In this Account, a series of studies applying 2D-IR to study the spectroscopy and dynamics of proteins in H 2 O-rich solvents is reviewed. A comparison of IR absorption spectroscopy and 2D-IR spectroscopy of protein-containing fluids is used to demonstrate the basis of the approach before a series of applications is presented. These range from measurements of fundamental protein biophysics to recent applications of machine learning to gain insight into protein−drug binding in complex mixtures. An outlook is presented, considering the potential for 2D-IR measurements to contribute to our understanding of protein behavior under nearphysiological conditions, along with an evaluation of the obstacles that still need to be overcome.

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Polyaspers A and B, the First Ergosterol‐Polyether Adducts with Unprecedented 6/6/6/5/5/6/6/6/6 Nonacyclic Architecture from Aspergillus sp. TJ507

Hu,

Li,

Shi

et al. 2023

Chin. J. Chem.

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Comprehensive SummaryPsoriasis is a chronic immune‐mediated inflammatory skin disease and the TNF‐α is an important therapeutic target of this disease. In our continuous study of bioactive natural products from fungi, the first ergosterol‐polyether adducts, polyaspers A (1) and B (2), along with two known ergosterols, (3β,5α,6α,22E)‐5,6‐epoxy‐3‐hydroxyergosta‐8,22‐dien‐7‐one (3) and calvasterol B (4), were isolated from Aspergillus sp. TJ507. Structure elucidation was accomplished by extensive spectroscopic analysis and single‐crystal X‐ray diffraction tests. Polyaspers A and B possessing an unequalled 6/6/6/5/5/6/6/6/6 nonacyclic system, and their biosynthetic pathways were proposed to include intermolecular cyclization and Diels‐Alder reactions. Activity screen of these isolates showed that 1—3 could improve the cell viability in an actinomycin D/TNF‐α induced L929 cells death model, with the EC50 values of 49.85, 46.75 and 4.99 μmol/L, respectively, and the activity of 3 was even comparable with that of the positive control SPD304. Further bioactive investigations discovered 3 could suppress the inflammatory response simulated with TNF‐α in HaCaT cells. In an imiquimod‐induced psoriasis murine model, 3 significantly restrained the development of psoriasis symptoms and reduced the expression of IL‐17 and IL‐23, presenting an anti‐psoriatic effect. As such, those ergosterol derivatives, might serve as lead compounds for the development of novel TNF‐α inhibitory agents in the clinical treatment of psoriasis.

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Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

Abstract: Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we combine...

Cited by 3 publications

References 52 publications

Biomolecular infrared spectroscopy: making time for dynamics

Biomolecular infrared spectroscopy: making time for dynamics

Using 2D-IR Spectroscopy to Measure the Structure, Dynamics, and Intermolecular Interactions of Proteins in H₂O

Polyaspers A and B, the First Ergosterol‐Polyether Adducts with Unprecedented 6/6/6/5/5/6/6/6/6 Nonacyclic Architecture from Aspergillus sp. TJ507

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Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

Abstract: Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we combine...

Cited by 3 publications

References 52 publications

Biomolecular infrared spectroscopy: making time for dynamics

Biomolecular infrared spectroscopy: making time for dynamics

Using 2D-IR Spectroscopy to Measure the Structure, Dynamics, and Intermolecular Interactions of Proteins in H2O

Polyaspers A and B, the First Ergosterol‐Polyether Adducts with Unprecedented 6/6/6/5/5/6/6/6/6 Nonacyclic Architecture from Aspergillus sp. TJ507

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Using 2D-IR Spectroscopy to Measure the Structure, Dynamics, and Intermolecular Interactions of Proteins in H₂O