Conformational changes

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Detection of the conformational changes of Discosoma red fluorescent proteins adhered on silver nanoparticles-based nanocomposites via surface-enhanced Raman scattering

Detection of the conformational changes of Discosoma red fluorescent proteins adhered on silver nanoparticles-based nanocomposites via surface-enhanced Raman scattering

6 Laboratoire de Physique Appliquée, Faculté des Sciences, Université de Sfax, BP 802, 3018 Sfax, Tunisia E-mail: kremena.makasheva@laplace.univ-tlse.fr Abstract Description of the relationship between protein structure and function remains a primary focus in molecular biology, biochemistry, protein engineering and bioelectronics. Moreover, the investigation of the protein conformational changes after adhesion and dehydration is of importance to tackle problems related to the interaction of proteins with solid surfaces. In this paper the conformational changes of wild-type Discosoma recombinant red fluorescent proteins (DsRed) adhered on silver nanoparticles (AgNPs)-based nanocomposites are explored via surface-enhanced Raman scattering (SERS). Originality in the present approach is to work on dehydrated DsRed thin protein layers in link with natural conditions during drying. To enable the SERS effect, plasmonic substrates consisting of a single layer of AgNPs encapsulated by an ultra-thin silica cover layer were elaborated by plasma process. The achieved enhancement of the electromagnetic field in the vicinity of the AgNPs is as high as 10 5 . This very strong
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Stability domains, substrate-induced conformational changes, and hinge-bending motions in a psychrophilic phosphoglycerate kinase: A microcalorimetric study

Stability domains, substrate-induced conformational changes, and hinge-bending motions in a psychrophilic phosphoglycerate kinase: A microcalorimetric study

interface of the N- and C-domains that have to move to bring the sub- strates in close proximity. Accordingly, the predominant weak stability of this enzyme can enhance the substrate-induced conformational changes (Figs. 6 and 7) and the resulting hinge-bending motions at low temperatures. It has also been suggested that during the course of evo- lution, some psychrophilic enzymes have reached a state close to the lowest stability compatible with the native state (17, 33, 35). This is supported here by the drastic effects of the single conservative muta- tions introduced in both N- and C-domains (Fig. 3), by the almost unfolded state of the double mutant (Fig. 3, inset) and by the lack of compact conformation of the structures forming the heat-labile DSC transition in the isolated domains (Figs. 4 and 5). As far as substrate binding is concerned, most psychrophilic enzymes have a reduced affin- ity arising from the active site mobility (33, 36), whereas PsPGK has a better affinity for the nucleotide. One can therefore propose that the heat-stable domain of PsPGK provides a more compact and structured nucleotide binding site which, consequently, has a high affinity. This seems to be an elegant molecular adaptation allowing the optimization of both k cat and K m at low temperatures, not previously observed in other psychrophilic enzymes.
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Understanding ribosome binding interactions and conformational changes of the EngA bacterial GTPase, a potential target for new antibiotics

Understanding ribosome binding interactions and conformational changes of the EngA bacterial GTPase, a potential target for new antibiotics

crystallised in a different space group from the wild-type, and the occurrence of non- crystallographic symmetry led to exposure of a substrate binding-site in one of the molecules in the asymmetric unit. Hence, we may think of residues that form crystal contacts involved in the conserved interface in EngA crystals that could be substituted in order to destabilise salt bridges or hydrogen bonds. E348, which forms a salt bridge, could be replaced by a reverse charge residue such as an arginine. R353 and Q355, which form hydrogen bonds, could be substituted by short side-chains, such as alanines, to avoid contacts. Similarly, substitution by bulky residues, such as tryptophans, could engender steric hindrance that would also prevent formation of crystal contacts. However, the approaches for crystal engineering cannot be generalised for all proteins and the results of point mutations may be difficult to predict in the context of the entire protein. In a study by Dale and co-workers, a rational prediction of crystal contacts was applied to a wild-type and a trimethoprim-resistant dihydrofolate reductase from S. aureus. However, the same residues that generated close crystal interactions in the wild-type protein in a hexagonal crystal form, after insertion in the trimethoprim-resistant protein generated a tetragonal space group with different crystal contacts (Dale et al., 2003). Therefore, this approach has to be adapted to each case. Particular attention may be needed in the search for a new conformation of EngA, as mutations intended to disrupt crystal contacts may also affect conformational changes. Namely, the main crystal interface that occurs in our EngA crystals is largely formed by residues from the α6-helix of GD2 that, according to the interpretation of our limited proteolysis assay, may have different surface environments in the GDP- or GTP-bound forms. If specific protein-protein interactions are disrupted upon site-directed mutagenesis, we may still not be able to obtain the biologically relevant GTP-bound conformation.
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High concentrations of GTP induce conformational changes in the essential bacterial GTPase EngA and enhance its binding to the ribosome

High concentrations of GTP induce conformational changes in the essential bacterial GTPase EngA and enhance its binding to the ribosome

EngA is a conserved bacterial GTPase involved in ribosome biogenesis. While essential in bacteria, EngA does not have any human orthologue and can thus be an interesting target for new antibacterial compounds. EngA is the only known GTPase bearing two G domains, making unique its catalytic cycle and the induced modulation of its conformation and interaction with the ribosome. We have investigated nucleotide-induced conformational changes in EngA in order to unveil their role in ribosome binding. SAXS and limited proteolysis were used to probe EngA confor- mational changes, and revealed a change in protein structure and a distinct rate of proteolysis induced by GTP. Structure analysis showed that the conformation adopted in solution in the presence of GTP does not match any known EngA structure, while the SAXS data measured in the presence of GDP are in perfect agreement with two crystal structures (i.e. 2HGJ and 4DCU). Combination of mass spectrometry and N-terminal sequenc- ing for the analysis of the fragmentation pattern upon proteolytic cleavage gave insights into which regions become more or less accessible in the dif- ferent nucleotide-bound states. Interactions studies confirmed a stronger binding of EngA to the bacterial ribosome in the presence of GTP and suggest that the induced change in conformation of EngA plays a key role for ribosome binding.
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Conformational changes in antibody Fab fragments upon binding and their consequences on the performance of docking algorithms

Conformational changes in antibody Fab fragments upon binding and their consequences on the performance of docking algorithms

Vreven and co-workers also assessed the expected difficulty of docking on each case based on the interface atoms RMSD and the number of non native contacts in aligned unbound structures. Of course, the result is highly correlated to the level of conformational changes at the interface, even though it is smoothed over the whole binding site. Nevertheless, separating the different components of the antibody gives a more precise insight into what actually constitutes a challenge for docking algorithms. Indeed, among the new antibody- antigen cases, none is expected to be difficult according to the classification by Vreven and co- workers yet many of them yield very poor or no results. Looking at the conformational changes of each component of the Fab fragment, we can see that a very large movement of a single CDR loop will more likely make the case difficult than a higher positional RMSD over the whole Fv fragment, even though both are obviously correlated.
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Crystallographic Evidence of Drastic Conformational Changes in the Active Site of a Flavin-Dependent

Crystallographic Evidence of Drastic Conformational Changes in the Active Site of a Flavin-Dependent

In summary, we have observed drastic di fferences in the active site of a flavin-dependent N-hydroxylase through a series of crystallographic snapshots. On the basis of these snapshots, we propose that KtzI, and other N-hydroxylases, will use a “flapping” flavin to help eject spent NADP + from their active sites following turnover, providing a molecular explanation for how these enzymes reset for the next round of catalysis. Considering that the mechanism for NADP + ejection has been enigmatic for all class B monooxygenases, it is tempting to speculate that flavin conformational changes could also be involved. Before this work, mobile flavins were only associated with PHBH-like “cautious” enzymes, whereas now we find flavin movement in an enzyme that is best defined as a “bold” monoxygenase. Although the trigger for flavin movement appears di fferent in these two distinct enzyme classes, in both cases, the flavin movement appears to be associated with a strategy for preventing uncoupling of the reductive and oxidative half-reactions. We hope that our structural observa- tions will provide a new lens for further biochemical examination of these interesting flavoenzymes.
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A unique ferrous iron binding mode is associated to large conformational changes for the transport protein FpvC of Pseudomonas aeruginosa

A unique ferrous iron binding mode is associated to large conformational changes for the transport protein FpvC of Pseudomonas aeruginosa

Accepted Article FpvC displays large conformational changes. All attempts to crystallize FpvC in its apo form were unsuccessful. Thus, we circumvented the issue by using FpvC-H6G, a mutant in which the six metal- liganded histidines were replaced by glycine residues to mimic the metal-free SBP. Indeed, FpvC- H6G is no longer able to bind a metal ion[12]. All of the six histidines belong to loop regions connecting secondary structural elements, therefore mutating them will likely not affect the secondary structure of the protein. To check this, we determined and compared the secondary structure of apo FpvC and FpvC-H6G mutant by circular dichroïsm. Both proteins share the same secondary structure content in line with what is observed in the crystal structure of FpvC-H6G (Figures 3 and 4 and Table 3). The 2.1 Å structure of FpvC-H6G contains two very similar molecules in the asymmetric unit as indicates the average RMSD of 0.66 Å for all Cα atoms. The structure reveals an open conformation with the site including the 6 Gly residues exposed to the solvent. In contrast to the metal-liganded structures, the full protein is defined in the electron density maps and the flexible loop (residues 132- 141) is now very well defined and includes an extra helix (residues 135-139) (Figure 4a).
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Tailored SU-8 micropillars superhydrophobic surfaces enhance conformational changes in breast cancer biomarkers

Tailored SU-8 micropillars superhydrophobic surfaces enhance conformational changes in breast cancer biomarkers

Here we report the fabrication of lotus-leaves-like tailored SU8 micropillars and their application in the context of a multi-technique characterization protocol for the investigation of the structural properties of the two estrogen receptors (ERα66/ERα46). ER (α) expression is undoubtedly the most important biomarker in breast cancer, because it provides the index for sensitivity to endocrine treatment. Beside the well-characterized ERα66 isoform, a shorter one (ERα46) was reported to be expressed in breast cancer cell line. The superhydrophobic supports were developed by using a double step approach including an optical lithography process and a plasma reactive ion roughening one. Upon drying on the micropillars, the bio-samples resulted in stretched fibers of different diameters which were then characterized by synchrotron X-ray diffraction (XRD), Raman and FTIR spectroscopy. The evidence of both different spectroscopic vibrational responses and XRD signatures in the two estrogen receptors suggests the presence of conformational changes between the two biomarkers. The SU8 micropillar platform therefore represents a valid tool to enhance the discrimination sensitivity of structural features of this class of biocompunds by exploiting a multi-technique in-situ characterization approach.
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Binding of moesin and ezrin to membranes containing phosphatidylinositol (4,5) bisphosphate: A comparative study of the affinity constants and conformational changes

Binding of moesin and ezrin to membranes containing phosphatidylinositol (4,5) bisphosphate: A comparative study of the affinity constants and conformational changes

for full length ezrin values of 71 %  -helix, which were above the X-ray predictions, 18% for random coils and only of 4 %  sheets [33], which were both below the X-ray predictions. The most prominent change observed after binding to PIP 2 -LUVs was a decrease of the proportion of  -helices in favour of random coil structures (Fig. 8 and Table 1). Which protein domain is more likely to be affected? A first tempting hypothesis is the  -helical linker that may unwind after molecule opening. However, the isolated linker domain of radixin was described as a stable  helical rod of an unusual length [35]. Conformational changes may also take place in the FERM domain, which is directly affected by membrane binding. Comparison of crystallographic data on the FERM domain in the absence [36] or presence of the C-terminal domain [14] or of IP 3 [37] showed essentially the same
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Structure of a [2Fe-2S] ferredoxin from Rhodobacter capsulatus likely involved in Fe-S cluster biogenesis and conformational changes observed upon reduction

Structure of a [2Fe-2S] ferredoxin from Rhodobacter capsulatus likely involved in Fe-S cluster biogenesis and conformational changes observed upon reduction

Structure of a [2Fe-2S] ferredoxin from Rhodobacter capsulatus likely involved in Fe-S cluster biogenesis and conformational changes observed upon reduction.4. Structure of a [2Fe-2S] fe[r]

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Conformational changes induced by phosphorylation of the FixJ receiver domain

Conformational changes induced by phosphorylation of the FixJ receiver domain

is a glutamic acid. Its substitution by lysine reduces the rate of autodephosphorylation considerably [38]. Different molecular events may be required for response regulators to adopt their functionally activated states. Typical situations are illustrated by the two-domain response regulators NarL and CheB, which are negatively regulated by their receiver domains. The methylesterase CheB modulates the signaling activity of the bacterial chemotaxis receptors. The X-ray structure of the unphos- phorylated full-length protein showed that the α 4– β 5– α 5 surface of the receiver domain is tightly packed against the C-terminal domain, preventing access to its catalytic site [9]. The phosphorylation-induced conformational changes of this region illustrated in FixJ explain the dis- ruption of this interface and the relieved inhibition of the catalytic domain [41]. In NarL the DNA-binding domain provides critical contacts to the receiver domain at the C-terminal parts of helices α 3 and α 4 [7]. Although this protein–protein interface is quite different from that found in CheB, it involves regions that relay the signal of phosphorylation (Figure 4a) and may favor the displace- ment of the output domain in phosphorylated NarL. In the case of FixJ, available data suggest a direct inhibitory interaction between the receiver domain and the tran- scription-activation domain [22,23]. It is straightforward to envision how the drastic conformational change demon- strated here may disrupt this interaction, thereby releasing DNA-binding activity of the FixJ C-terminal domain and resulting in transcriptional activation.
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Nonlinear dynamics and conformational changes of linear entangled polymers using the Rolie-Poly model with an “effective” maximum contour length

Nonlinear dynamics and conformational changes of linear entangled polymers using the Rolie-Poly model with an “effective” maximum contour length

/ La version de cette publication peut être l’une des suivantes : la version prépublication de l’auteur, la version acceptée du manuscrit ou la version de l’éditeur. Access and use of [r]

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Conformational Changes of Bovine Serum Albumin Induced by Adsorption on Different Clay Surfaces: FTIR Analysis

Conformational Changes of Bovine Serum Albumin Induced by Adsorption on Different Clay Surfaces: FTIR Analysis

We emphasize on the importance of electrostatic forces in protein adsorption processes whether adsorptive minerals are negatively charged or neutral. In the first case, the charges on the side chains influence the adsorption as a function of p 2 H. In the second case, hydrophobic interactions at the protein-clay interface may also distort bundled domains at various distances from the interface. Asp, Glu and His side chains play a major role in both ternary and secondary BSA structures. For p 2 H large enough to ensure complete Asp and Glu deprotonation, the major p 2 H and adsorption effects are already established after 10 min. For low p 2 H, when Asp and Glu are protonated, slow conformational rearrangements depend on protein concentration and on the adsorptive surfaces leading to different structures with various protein self-association over protein hydration ratio.
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Conformational changes influence clogging behavior of micrometer-sized microgels in idealized multiple constrictions

Conformational changes influence clogging behavior of micrometer-sized microgels in idealized multiple constrictions

Discussion In previous work 24 , we investigated the behavior of microgel packings at different osmotic pressures, and found that microgels use both deswelling and deformation to accommodate pressure to different extents. The compo- sition of the microgels changes with increasing pressure since they lose volume, becoming more concentrated which also influences their deswelling and deformation behavior. In our current observations (microgels under dynamic conditions) we see that this also holds. The microgels both deform and lose volume to accommodate applied forces as illustrated in Fig.  7 , albeit that in our previous work the microgels were part of a packing and experienced an isotropic pressure. This is not the case in the current work in which microgels experience an anisotropic pressure while being forced through a constriction. In order to deform and deswell and go through a constriction, the microgels have the modify themselves in a much more dynamic way, deswelling and reswelling occur continuously and simultaneously. Also the extent of local particle modification was higher as for the iso- tropic pressure case, especially when the microgels are much bigger than the constriction aperture.
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Monitoring Conformational Changes in an Enzyme Conversion Inhibitor Using Pure Shift Exchange NMR Spectroscopy

Monitoring Conformational Changes in an Enzyme Conversion Inhibitor Using Pure Shift Exchange NMR Spectroscopy

The pulse sequence, the resulting 2D EXSY spectrum (recorded with τ m = 1.2 s), and a comparison of selected correlations from standard EXSY, F2-PSYCHE-EXSY and F1- PSYCHE-EXSY spectra are provided in ESI. Very similar resolution was achieved along the pure shift dimension in both experi- ments. We remark that the 2D F1-PSYCHE-EXSY was recorded in 8 hours, which is shorter than the 14 hours needed to record the F2-PSYCHE-EXSY spectrum with similar resolution, using the pseudo-3D acquisition scheme. The gain in experimental time is however not as substantial as it could be expected, due to the fact that a high number of increments needs to be recorded in the F1-PSYCHE-EXSY to reconstruct the indirect time domain and benefit from the resolution enhancement brought by the pure shift block. In the following, we are interested in evaluating the potential of the F2-PSYCHE-EXSY approach for the analysis of the conformational exchange process, and notably to describe the impact of the artefacts that arise from the reconstruction of the pure shift FID from a series of data chunks. Indeed, the results shown above suggest that the interconversion process between conformers A and B can be probed with a better accuracy, on a higher number of resolved proton sites using the F2-PSYCHE-EXSY approach. Following on from these results, we have studied the influence of the quality of these data on the determination of the kinetic and thermodynamic parameters of the conformational exchange. We have recorded a series of F2-PSYCHE-EXSY spectra with the mixing time τ m varied from 400 to 1200 ms, using the standard
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Ligand-Induced Conformational Changes with Cation Ejection upon Binding to Human Telomeric DNA G-Quadruplexes

Ligand-Induced Conformational Changes with Cation Ejection upon Binding to Human Telomeric DNA G-Quadruplexes

Circular dichroism spectroscopy indicates that the G‐quartets in the 1‐K +  form have alter‐ nated stacking.  In order to obtain information about conformational changes occurring upon ligand binding and  cation ejection, we performed CD experiments on the same solutions. The CD spectra give infor‐ mation on the stacking mode of consecutive guanines. Type‐I spectra (positive peak at 265 nm,  negative peak at 240 nm) indicate guanine stacking all in the same orientation (e.g., anti‐anti),  type‐II spectra (positive peaks at 265 and 295 nm, negative peak at 240 nm) indicate guanine stack‐ ing partly in the same, and partly in alternating orientation (e.g., anti‐syn or syn‐anti), and type‐ III spectra (positive peaks at 295 and 240 nm, negative peak at 260 nm) indicate guanine stacking  in  exclusively  alternating  orientations. 49   If  mixtures  are  present,  the  CD  spectrum  will  be  the  weighted average spectrum of all conformers present in solution and may resemble Type‐II spectra.  Figure 3A illustrates the CD spectral changes observed when adding ligands to 24TTG (hybrid‐1  structure with CD spectrum of Type II). In the case of Phen‐DC3, 360A and PDS, the CD spectra  are shifting to Type‐III, indicating exclusively alternated stacking. In the corresponding ESI‐MS  spectra, almost all 24TTG is bound to 360A or Phen‐DC3 in a 1:1:1 (DNA:ligand:K + ) stoichiometry.  The 1‐K +  and presumably 2‐quartet, ligand‐bound structure has therefore the alternate G‐quartet  stacking typically encountered in antiparallel folds. For PDS, ESI‐MS tells us that some free 24TTG  remains, explaining the lesser shift of the CD spectrum compared to 360A and Phen‐DC3, but the  ligand‐bound structure has the same characterisctics. In the cases of TrisQ and L2H2, the CD spec‐ tra of 24TTG are almost unaffected. The same results are obtained for 26TTA, 23TAG and 22GT  (supporting Figures S13, S14 an S15, respectively).  
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Conjugated polymers and designed interfaces : conformational analysis and applications

Conjugated polymers and designed interfaces : conformational analysis and applications

The conformations of conjugated polymers can be altered by nearby environments. The intrapolymer conformation and interpolymer assemblies have a crucial impact on a variety of properties such as absorption, energy migration, and fluorescence. In this dissertation, the conformational changes and their effects on photophysics in different environments will be discussed. In Chapter 1, the basic principles to understand this thesis will be reviewed, including the processes of absorption and emission, exciton migration, the Langmuir–Blodgett technique, and interfacial phenomena. In Chapter 2, the conformational control and alignment of conjugated polymers at the air–water interface and how this alignment of polymers can lead to new emissive aggregates will be presented. The emission has the characteristics of excimers with the improved fluorescence quantum yields. The transfer of the aligned aggregates to glass substrates is attempted and these excimer films undergo reorganization upon exposure to solvent vapors, which triggers the fluorescence color change from yellow to cyan, leading to fluorescence-based chemical sensors. In Chapter 3, exciton migration to low-energy emissive traps at amphiphilic interfaces will be discussed. This chapter will deliver the design of interfaces and how the exciton migration can occur at the air–water interface and the hydrocarbon–water interface in lyotropic liquid crystals. To expand this interfacial exciton migration to more generalizable interfaces, Chapter 4 will show the fabrication of oil-in-water emulsions and how exciton migration in oil-in-water emulsion can produce distinct fluorescences between solution and interfaces. Chapter 5 will discuss the structural variations of novel functional conjugated polymers and how substituents can change the conformation of the polymer backbones. Additionally, how this conformational change affects the electronic and optical properties of polymers will be examined.
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Conformational adaptation of UNCG loops upon crowding

Conformational adaptation of UNCG loops upon crowding

In the present study, we report observations from crystal structures of two different ribozymes, where a given UUCG loop adopts two distinct conformations according to the crystal packing variations resulting from slight structural changes of the RNA in the asymmetric unit. In each case, the UUCG loops were engineered in order to stabilize the underlying stem and thus, facilitate crystallization of the RNA molecule. Although the aim of these strategies was not to promote inter-molecular interactions, the engi- neered UUCG loops become involved in crystal packing contacts, which resulted in squashing these loops. The conformations induced by these interactions are very sim- ilar, and reveal that the squashed conformation is specifi- cally obtained in response to the backbone –backbone interaction through contacts between phosphate and 2 ′ hydroxyl groups. In the two occurrences of this interac- tion observed in our crystal structures, a helix of a symme- try-related molecule contacts the tip of the loop formed by the second and third residues (Fig. 3). However, in the crys- tal structure of the group II ribozyme, the guanine (L4) of the squashed loop does not interact with a symmetry-relat- ed RNA like it does in the CP LC ribozyme crystal structure. This indicates that G-mediated tertiary interaction is not a prerequisite to the folding of the squashed conformation. The relevance of the distorted UUCG loop conformation we observe is supported by the behavior of specific loops in ribosomal RNAs. Interestingly, the UACG loop from cluster 41 in the study of Bottaro and Lindorff-Larsen (2017) adopts the squashed conformation only in the con- text of the 70S ribosome since the same loop adopts a ca- nonical conformation in the original structure of the 30S ribosomal subunit (Wimberly et al. 2000). Subunit associa- tion is well known to induce RNA conformational changes, suggesting that the one we describe in the context of the ribosome may have a biological significance. Inspection of the other clusters reveals that loops with other sequences can indeed adopt conformations very much related to the squashed loop from the LC ribozyme. The L2 nucleotide presents the most variable position. Residues at positions 3 and 4 occupy very identical positions in spite of belong- ing to different clusters (Table 3). It appears that the cen- troid approach developed by Bottaro and Lindorff-Larsen may be too sensitive, and that some clusters could actually be merged under more general structural features.
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Geometric algorithms for the conformational analysis of long protein loops

Geometric algorithms for the conformational analysis of long protein loops

Unite´ de Recherches sur la Biocatalyse, 2 rue de la Houssinie`re, 44322 Nantes, France Abstract: The efficient filtering of unfeasible conformations would considerably benefit the exploration of the conformational space when searching for minimum energy structures or during molecular simulation. The most important conditions for filtering are the maintenance of molecular chain integrity and the avoidance of steric clashes. These conditions can be seen as geometric constraints on a molecular model. In this article, we discuss how techniques issued from recent research in robotics can be applied to this filtering. Two complementary techniques are presented: one for conformational sampling and another for computing conformational changes satisfying such geometric constraints. The main interest of the proposed techniques is their application to the structural analysis of long protein loops. First experimental results demonstrate the efficacy of the approach for studying the mobility of loop 7 in amylosucrase from Neisseria polysaccharea. The supposed motions of this 17-residue loop would play an important role in the activity of this enzyme.
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Conformational pathway provides unique sensitivity to a synaptic mGluR

Conformational pathway provides unique sensitivity to a synaptic mGluR

Metabotropic glutamate receptors (mGluRs) are dimeric G-protein–coupled receptors that operate at synapses. Macroscopic and single molecule FRET to monitor structural rearran- gements in the ligand binding domain (LBD) of the mGluR7/7 homodimer revealed it to have an apparent af finity ~4000-fold lower than other mGluRs and a maximal activation of only ~10%, seemingly too low for activation at synapses. However, mGluR7 heterodimerizes, and we find it to associate with mGluR2 in the hippocampus. Strikingly, the mGluR2/7 hetero- dimer has high af finity and efficacy. mGluR2/7 shows cooperativity in which an unliganded subunit greatly enhances activation by agonist bound to its heteromeric partner, and a unique conformational pathway to activation, in which mGluR2/7 partially activates in the Apo state, even when its LBDs are held open by antagonist. High sensitivity and an unusually broad dynamic range should enable mGluR2/7 to respond to both glutamate transients from nearby release and spillover from distant synapses.
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