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Side-Chain Dynamics of the ?1B-Adrenergic Receptor determined by NMR via Methyl Relaxation |
Oct 09, 2023 - 4:39 PM - by nmrlearner
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Side-Chain Dynamics of the ?1B-Adrenergic Receptor determined by NMR via Methyl Relaxation
Abstract
G protein-coupled receptors (GPCRs) are medically important membrane proteins that sample inactive, intermediate, and active conformational states characterized by relatively slow interconversions (~?s–ms). On a faster timescale (~ps–ns), the conformational landscape of GPCRs is governed by the rapid dynamics of amino acid side chains. Such dynamics are essential for protein functions such as ligand recognition and allostery. Unfortunately, technical challenges have almost entirely precluded the study of side-chain dynamics for GPCRs. Here, we investigate the rapid side-chain dynamics of a thermostabilized ?1B-adrenergic receptor (?1B-AR) as probed by methyl relaxation. We determined order parameters for Ile, Leu, and Val methyl groups in the presence of inverse agonists that bind orthosterically (prazosin, tamsulosin) or allosterically (conopeptide ?-TIA). Despite the differences in the ligands, the receptor's overall side-chain dynamics are very similar, including those of the apo form. However, ?-TIA increases the flexibility of Ile1764x56 and possibly of Ile2145x49, adjacent to Pro2155x50 of the highly conserved P5x50I3x40F6x44 motif crucial for receptor activation, suggesting differences in the mechanisms for orthosteric and allosteric receptor inactivation. Overall, increased Ile side-chain rigidity was found for residues closer to the center of the membrane bilayer, correlating with denser packing and lower protein surface exposure. In contrast to two microbial membrane proteins, in ?1B-AR Leu exhibited higher flexibility than Ile side chains on average, correlating with the presence of Leu in less densely packed areas and with higher protein-surface... [Read More]
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0 Replies | 304 Views
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Breaking boundaries: TINTO in POKY for computer vision-based NMR walking strategies |
Oct 08, 2023 - 4:31 AM - by nmrlearner
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Breaking boundaries: TINTO in POKY for computer vision-based NMR walking strategies
Abstract
Nuclear magnetic resonance is a crucial technique for studying biological complexes, as it provides precise structural and dynamic information at the atomic level. However, the process of assigning resonances can be time-consuming and challenging, particularly in cases where peaks overlap, or the data quality is poor. In this paper, we present TINTO (Two and three-dimensional Imaging for NMR sTrip Operation via CV/ML), an advanced semiautomatic toolset for NMR resonance assignment. TINTO comprises two separate tools, each tailored for either two-dimensional or three-dimensional imaging. The toolset utilizes a computer-vision approach and a machine learning approach, specifically structural similarity index and principal components analysis, to perform visual similarity searches of resonances and quickly locate similar strips, and in that way overcome the challenges associated with peak overlap without requiring peak picking. Our tool offers a user-friendly interface and has the potential to enhance the efficiency and accuracy of NMR resonance assignment, particularly in complex cases. This advancement holds promising implications for furthering our understanding of biological systems at the molecular level. TINTO is pre-installed in the POKY suite, which is available at https://poky.clas.ucdenver.edu.
Source: Journal of Biomolecular NMR
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0 Replies | 268 Views
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