Reorganization

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Jean-pierre Changeux - One of the best experts on this subject based on the ideXlab platform.

  • Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism.
    Biophysical Journal, 2005
    Co-Authors: Antoine Taly, Marc Delarue, Thomas Grutter, Michael Nilges, Nicolas Le Novere, Pierre-jean Corringer, Jean-pierre Changeux
    Abstract:

    We present a three-dimensional model of the homopentameric alpha7 nicotinic acetylcholine receptor (nAChR), that includes the extracellular and membrane domains, developed by comparative modeling on the basis of: 1), the x-ray crystal structure of the snail acetylcholine binding protein, an homolog of the extracellular domain of nAChRs; and 2), cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata nAChRs. We performed normal mode analysis on the complete three-dimensional model to explore protein flexibility. Among the first 10 lowest frequency modes, only the first mode produces a structural Reorganization compatible with channel gating: a wide opening of the channel pore caused by a concerted symmetrical quaternary twist motion of the protein with opposing rotations of the upper (extracellular) and lower (transmembrane) domains. Still, significant Reorganizations are observed within each subunit, that involve their bending at the domain interface, an increase of angle between the two beta-sheets composing the extracellular domain, the internal beta-sheet being significantly correlated to the movement of the M2 alpha-helical segment. This global symmetrical twist motion of the pentameric protein complex, which resembles the opening transition of other multimeric ion channels, reasonably accounts for the available experimental data and thus likely describes the nAChR gating process.

K N Houk - One of the best experts on this subject based on the ideXlab platform.

  • structural Reorganization and pReorganization in enzyme active sites comparisons of experimental and theoretically ideal active site geometries in the multistep serine esterase reaction cycle
    Journal of the American Chemical Society, 2008
    Co-Authors: Adam J T Smith, Roger Muller, Miguel D Toscano, Peter Kast, Homme W Hellinga, Donald Hilvert, K N Houk
    Abstract:

    Many enzymes catalyze reactions with multiple chemical steps, requiring the stabilization of multiple transition states during catalysis. Such enzymes must strike a balance between the conformational Reorganization required to stabilize multiple transition states of a reaction and the confines of a preorganized active site in the polypeptide tertiary structure. Here we investigate the compromise between structural Reorganization during the catalytic process and pReorganization of the active site for a multistep enzyme-catalyzed reaction, the hydrolysis of esters by the Ser-His-Asp/Glu catalytic triad. Quantum mechanical transition states were used to generate ensembles of geometries that can catalyze each individual step in the mechanism. These geometries are compared to each other by superpositions of catalytic atoms to find "consensus" geometries that can catalyze all steps with minimal rearrangement. These consensus geometries are found to be excellent matches for the natural active site. PReorganization is therefore found to be the major defining characteristic of the active site, and Reorganizational motions often proposed to promote catalysis have been minimized. The variability of enzyme active sites observed by X-ray crystallography was also investigated empirically. A catalog of geometrical parameters relating active site residues to each other and to bound inhibitors was collected from a set of crystal structures. The crystal-structure-derived values were then compared to the ranges found in quantum mechanically optimized structures along the entire reaction coordinate. The empirical ranges are found to encompass the theoretical ranges when thermal fluctuations are taken into account. Therefore, the active sites are preorganized to a geometry that can be objectively and quantitatively defined as minimizing conformational Reorganization while maintaining optimal transition state stabilization for every step during catalysis. The results provide a useful guiding principle for de novo design of enzymes with multistep mechanisms.

  • structural Reorganization and pReorganization in enzyme active sites comparisons of experimental and theoretically ideal active site geometries in the multistep serine esterase reaction cycle
    Journal of the American Chemical Society, 2008
    Co-Authors: Adam J T Smith, Roger Muller, Miguel D Toscano, Peter Kast, Homme W Hellinga, Donald Hilvert, K N Houk
    Abstract:

    Many enzymes catalyze reactions with multiple chemical steps, requiring the stabilization of multiple transition states during catalysis. Such enzymes must strike a balance between the conformational Reorganization required to stabilize multiple transition states of a reaction and the confines of a preorganized active site in the polypeptide tertiary structure. Here we investigate the compromise between structural Reorganization during the catalytic process and pReorganization of the active site for a multistep enzyme-catalyzed reaction, the hydrolysis of esters by the Ser-His-Asp/Glu catalytic triad. Quantum mechanical transition states were used to generate ensembles of geometries that can catalyze each individual step in the mechanism. These geometries are compared to each other by superpositions of catalytic atoms to find “consensus” geometries that can catalyze all steps with minimal rearrangement. These consensus geometries are found to be excellent matches for the natural active site. Preorganizati...

Antoine Taly - One of the best experts on this subject based on the ideXlab platform.

  • Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism.
    Biophysical Journal, 2005
    Co-Authors: Antoine Taly, Marc Delarue, Thomas Grutter, Michael Nilges, Nicolas Le Novere, Pierre-jean Corringer, Jean-pierre Changeux
    Abstract:

    We present a three-dimensional model of the homopentameric alpha7 nicotinic acetylcholine receptor (nAChR), that includes the extracellular and membrane domains, developed by comparative modeling on the basis of: 1), the x-ray crystal structure of the snail acetylcholine binding protein, an homolog of the extracellular domain of nAChRs; and 2), cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata nAChRs. We performed normal mode analysis on the complete three-dimensional model to explore protein flexibility. Among the first 10 lowest frequency modes, only the first mode produces a structural Reorganization compatible with channel gating: a wide opening of the channel pore caused by a concerted symmetrical quaternary twist motion of the protein with opposing rotations of the upper (extracellular) and lower (transmembrane) domains. Still, significant Reorganizations are observed within each subunit, that involve their bending at the domain interface, an increase of angle between the two beta-sheets composing the extracellular domain, the internal beta-sheet being significantly correlated to the movement of the M2 alpha-helical segment. This global symmetrical twist motion of the pentameric protein complex, which resembles the opening transition of other multimeric ion channels, reasonably accounts for the available experimental data and thus likely describes the nAChR gating process.

  • Normal mode analysis suggest a quaternary P.-J. Corringer et al
    2005
    Co-Authors: Antoine Taly
    Abstract:

    ABSTRACT We present a three-dimensional model of the homopentameric a7 nicotinic acetylcholine receptor (nAChR), that includes the extracellular and membrane domains, developed by comparative modeling on the basis of: 1), the x-ray crystal structure of the snail acetylcholine binding protein, an homolog of the extracellular domain of nAChRs; and 2), cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata nAChRs. We performed normal mode analysis on the complete three-dimensional model to explore protein flexibility. Among the first 10 lowest frequency modes, only the first mode produces a structural Reorganization compatible with channel gating: a wide opening of the channel pore caused by a concerted symmetrical quaternary twist motion of the protein with opposing rotations of the upper (extracellular) and lower (transmembrane) domains. Still, significant Reorganizations are observed within each subunit, that involve their bending at the domain interface, an increase of angle between the two b-sheets composing the extracellular domain, the internal b-sheet being significantly correlated to the movement of the M2 a-helical segment. This global symmetrical twist motion of the pentameric protein complex, which resembles the opening transition of other multimeric ion channels, reasonably accounts for the available experimental data and thus likely describes the nAChR gating process

Philip J Siddall - One of the best experts on this subject based on the ideXlab platform.

  • functional Reorganization of the brain in humans following spinal cord injury evidence for underlying changes in cortical anatomy
    The Journal of Neuroscience, 2011
    Co-Authors: Luke A Henderson, Sylvia M Gustin, Paul J Wrigley, Paul M Macey, Philip J Siddall
    Abstract:

    Loss of somatosensory drive results in functional Reorganization of the primary somatosensory cortex (SI). While the phenomenon of functional cortical Reorganization is well established, it remains unknown whether in humans, functional Reorganization results from changes in brain anatomy, or simply reflects an unmasking of already existing dormant synapses. In 20 subjects with complete thoracic spinal cord injuries (SCIs) and 23 controls, we used functional and structural magnetic resonance imaging to determine whether SI Reorganization was associated with changes in SI anatomy. SCI resulted in a significant SI Reorganization, with the little finger representation moving medially toward the lower body representation (i.e., area of sensory loss). Furthermore, although SCI was associated with gray matter volume loss in the lower body representation, this loss was minimized as Reorganization increased. That is, the greater the medial shift in little finger representation, the greater the gray matter preservation in the lower body representation. In addition, in the region of greatest SI Reorganization (little finger), fractional anisotropy was correlated with SI Reorganization. That is, as SI Reorganization increased, the extent of aligned structures decreased. Finally, although thalamocortical fibers remained unchanged, the ease and direction of water movement within the little finger representation was altered, being directed more toward the midline in SCI subjects. These data show that SI Reorganization following SCI is associated with changes in SI anatomy and provide compelling evidence that SI Reorganization in humans results from the growth of new lateral connections, and not simply from the unmasking of already existing lateral connections.

  • neuropathic pain and primary somatosensory cortex Reorganization following spinal cord injury
    Pain, 2009
    Co-Authors: Paul J Wrigley, Sylvia M Gustin, Luke A Henderson, S R Press, Vaughan G Macefield, Simon C Gandevia, Michael J Cousins, James W Middleton, Philip J Siddall
    Abstract:

    Abstract The most obvious impairments associated with spinal cord injury (SCI) are loss of sensation and motor control. However, many subjects with SCI also develop persistent neuropathic pain below the injury which is often severe, debilitating and refractory to treatment. The underlying mechanisms of persistent neuropathic SCI pain remain poorly understood. Reports in amputees describing phantom limb pain demonstrate a positive correlation between pain intensity and the amount of primary somatosensory cortex (S1) Reorganization. Of note, this S1 Reorganization has also been shown to reverse with pain reduction. It is unknown whether a similar association between S1 Reorganization and pain intensity exists in subjects with SCI. The aim of this investigation was to determine whether the degree of S1 Reorganization following SCI correlated with on-going neuropathic pain intensity. In 20 complete SCI subjects (10 with neuropathic pain, 10 without neuropathic pain) and 21 control subjects without SCI, the somatosensory cortex was mapped using functional magnetic resonance imaging during light brushing of the right little finger, thumb and lip. S1 Reorganization was demonstrated in SCI subjects with the little finger activation point moving medially towards the S1 region that would normally innervate the legs. The amount of S1 Reorganization in subjects with SCI significantly correlated with on-going pain intensity levels. This study provides evidence of a link between the degree of cortical Reorganization and the intensity of persistent neuropathic pain following SCI. Strategies aimed at reversing somatosensory cortical Reorganization may have therapeutic potential in central neuropathic pain.

Poste Amanda - One of the best experts on this subject based on the ideXlab platform.

  • Terrestrial Inputs Shape Coastal Bacterial and Archaeal Communities in a High Arctic Fjord (Isfjorden, Svalbard)
    'Frontiers Media SA', 2021
    Co-Authors: Delpech Lisa-marie, Vonnahme Tobias, Mcgovern Maeve, Gradinger Rolf, Præbel Kim, Poste Amanda
    Abstract:

    The Arctic is experiencing dramatic changes including increases in precipitation, glacial melt, and permafrost thaw, resulting in increasing freshwater runoff to coastal waters. During the melt season, terrestrial runoff delivers carbon- and nutrient-rich freshwater to Arctic coastal waters, with unknown consequences for the microbial communities that play a key role in determining the cycling and fate of terrestrial matter at the land-ocean interface. To determine the impacts of runoff on coastal microbial (bacteria and archaea) communities, we investigated changes in pelagic microbial community structure between the early (June) and late (August) melt season in 2018 in the Isfjorden system (Svalbard). Amplicon sequences of the 16S rRNA gene were generated from water column, river and sediment samples collected in Isfjorden along fjord transects from shallow river estuaries and glacier fronts to the outer fjord. Community shifts were investigated in relation to environmental gradients, and compared to river and marine sediment microbial communities. We identified strong temporal and spatial Reorganizations in the structure and composition of microbial communities during the summer months in relation to environmental conditions. Microbial diversity patterns highlighted a Reorganization from rich communities in June toward more even and less rich communities in August. In June, waters enriched in dissolved organic carbon (DOC) provided a niche for copiotrophic taxa including Sulfitobacter and Octadecabacter. In August, lower DOC concentrations and Atlantic water inflow coincided with a shift toward more cosmopolitan taxa usually associated with summer stratified periods (e.g., SAR11 Clade Ia), and prevalent oligotrophic marine clades (OM60, SAR92). Higher riverine inputs of dissolved inorganic nutrients and suspended particulate matter also contributed to spatial Reorganizations of communities in August. Sentinel taxa of this late summer fjord environment included taxa from the class Verrucomicrobiae (Roseibacillus, Luteolibacter), potentially indicative of a higher fraction of particle-attached bacteria. This study highlights the ecological relevance of terrestrial runoff for Arctic coastal microbial communities and how its impacts on biogeochemical conditions may make these communities susceptible to climate change

  • Terrestrial Inputs Shape Coastal Bacterial and Archaeal Communities in a High Arctic Fjord (Isfjorden, Svalbard)
    'Frontiers Media SA', 2021
    Co-Authors: Delpech Lisa-marie, Vonnahme Tobias, Mcgovern Maeve, Gradinger Rolf, Præbel Kim, Poste Amanda
    Abstract:

    The Arctic is experiencing dramatic changes including increases in precipitation, glacial melt, and permafrost thaw, resulting in increasing freshwater runoff to coastal waters. During the melt season, terrestrial runoff delivers carbon- and nutrient-rich freshwater to Arctic coastal waters, with unknown consequences for the microbial communities that play a key role in determining the cycling and fate of terrestrial matter at the land-ocean interface. To determine the impacts of runoff on coastal microbial (bacteria and archaea) communities, we investigated changes in pelagic microbial community structure between the early (June) and late (August) melt season in 2018 in the Isfjorden system (Svalbard). Amplicon sequences of the 16S rRNA gene were generated from water column, river and sediment samples collected in Isfjorden along fjord transects from shallow river estuaries and glacier fronts to the outer fjord. Community shifts were investigated in relation to environmental gradients, and compared to river and marine sediment microbial communities. We identified strong temporal and spatial Reorganizations in the structure and composition of microbial communities during the summer months in relation to environmental conditions. Microbial diversity patterns highlighted a Reorganization from rich communities in June toward more even and less rich communities in August. In June, waters enriched in dissolved organic carbon (DOC) provided a niche for copiotrophic taxa including Sulfitobacter and Octadecabacter. In August, lower DOC concentrations and Atlantic water inflow coincided with a shift toward more cosmopolitan taxa usually associated with summer stratified periods (e.g., SAR11 Clade Ia), and prevalent oligotrophic marine clades (OM60, SAR92). Higher riverine inputs of dissolved inorganic nutrients and suspended particulate matter also contributed to spatial Reorganizations of communities in August. Sentinel taxa of this late summer fjord environment included taxa from the class Verrucomicrobiae (Roseibacillus, Luteolibacter), potentially indicative of a higher fraction of particle-attached bacteria. This study highlights the ecological relevance of terrestrial runoff for Arctic coastal microbial communities and how its impacts on biogeochemical conditions may make these communities susceptible to climate change.publishedVersio