Fig 3 - uploaded by Jean-Francois Gibrat
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3 Left panel: lateral view of the β2 adrenergic receptor ( light blue is the activated conformation and light brown is the inactive conformation). The bottom of the panel corresponds to the cytoplasmic region. Right panel: view of the cytoplasmic region of the receptor. Cytoplasmic loops have been removed for clarity. TMH6 displays a 14 Å outward movement in the activated state. TMH5 shows a smaller outward movement and a 7-residue extension of the helix
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Bioelectronic noses can utilize olfactory receptors (ORs) as recognition elements. This chapter describes biochemical characteristics of these OR proteins. ORs being G protein-coupled receptors (GPCRs) are integral membrane proteins composed of seven transmembrane spanning helices. In mammals, there exist as many as 1,000 OR genes accounting for ab...
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... structure of the Human chemokine CXCR1 receptor obtained by solid-state NMR [28], all other 3D structures have been solved by X-ray crystallography and feature complexes of the receptors with different types of ligands (agonists, partial agonists, biased agonists, inverse agonists, antagonists, selective antagonists, irreversible antagonists, see Fig. 3.1 for definitions of these terms). In the structures of receptor-antagonist/inverse agonist complexes the receptors adopt an inactive conformation. In 2012, the structures of a number of receptor-agonist complexes (see Table 3.1) have been solved, stabilized by the introduction of a camelid antibody fragment (nanobody) [29]. The ...
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... within the 7TMD is thus identified by two numbers: the TMH number and a number indicating its relative position with respect to the most conserved one in this TMH. For instance, 7.49 represents the residue preceding the most conserved one (a Proline) in the TMH7 sequence. Ballesteros-Weinstein 50 (N50) residues are highlighted in yellow in Fig. 3.2. Functionally important sequence motifs for GPCRs are also found in the TMHs (shown in bold in Fig. 3.2), for instance the D [E]RY motif at the end of TMH3 that is part of a "ionic lock", the FxxCWxP motif in TMH6 and NPxxY motif at the end of TMH7 that are suspected to be involved in the activation mechanisms (see next section). The ...
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... binding of the agonist, small conformational changes in the ligand-binding extracellular side are amplified in the cytoplasmic side leading, more conspicuously, to a large structural rearrangement of TMH6 (14 Å outward movement) and a smaller outward movement and 7-residue cytoplasmic helix extension of TMH5 (see Fig. 3.3) [30]. According to Venkatakrishnan and coll. [34] the sequence of events is the following: (i) agonist binding causes a small local structural change in the Pro 5.50 that induces a distortion of TMH5, (ii) there is a relocation of TMH3 and TMH7 (in the β2 adrenergic and A 2A adenosine receptors the agonist ligand pulls the ...
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... exist several activated conformational states, and that different ligands are able to shift the equilibrium between these states. Nygaard and coll., using NMR techniques complemented with molecular dynamics simulations, have studied the existence of conformational states not observed in crystal structures [37]. They propose the model shown in Fig. 3.4 to explain the GPCR activation mechanisms. There are three types of conformational states: inactive, intermediate and activated. Each state consists of several microstates in which the receptor adopts slightly different conformations. The probability of finding the system in a given state depends on the free energy of this state. Free ...
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... with increasing concentrations of odorants [56,57], in apparent contradiction with the sigmoid curves observed in natural tissues for the OR/ligand interaction [58,59], resulted in a model of OR activation involving allosteric modulation of OR activity by odorant binding proteins (OBPs) [60] and binding cooperativity within an OR homodimer [61] (Fig. 3.5). Indeed, it was demonstrated that OBPs can bind ORs [62] and they restore OR activity at high odorant doses [60], probably by exerting an allosteric control of OR activity within an OR dimer. ORs were shown to exist as constitutive homodimers by bioluminescence resonance energy transfer (BRET) and to display different con-formational ...
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... odorant doses [60], probably by exerting an allosteric control of OR activity within an OR dimer. ORs were shown to exist as constitutive homodimers by bioluminescence resonance energy transfer (BRET) and to display different con-formational changes upon stimulation with various odorant doses, corresponding to different levels of activity [61] (Fig. 3.6): (i) low and moderate odorant doses (below the micromolar) induce an increase of the initial BRET level, showing a conformational change of the OR dimers which are activated at these odorant doses, (ii) whereas higher odorant doses induce a lesser increase or no increase at all of the initial BRET level, indicating another ...
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... or no increase at all of the initial BRET level, indicating another conformation of the OR dimers, which corresponds to a decreased activity. It was thus assumed that at low and moderate odorant doses, only one odorant molecule could bind to the OR dimer on one protomer, this binding inducing a conformational change of the second protomer and a Fig. 3.5 Effect of OBP-1F on helional detection by OR17-40 assayed by Surface Plasmon Resonance (redrawn from [60]). Each curve is plotted as the difference in response to helional relative to controls obtained by replacing the odorant with water. The SPR shift amplitude is shown as a function of the helional concentration, without or with ...
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... (redrawn from [60]). Each curve is plotted as the difference in response to helional relative to controls obtained by replacing the odorant with water. The SPR shift amplitude is shown as a function of the helional concentration, without or with OBP-1F. The OBP restores OR activity at high odorant dose, from a bell-shaped to a sigmoid curve Fig. 3.6 a Surface Plasmon Resonance (SPR) response (RU: relative units) obtained from the stimulation of the OR17-40 receptor with helional (agonist) or vanillin (negative control odorant) at different concentrations. A schematic representation of the proposed molecular mechanism for odorant interaction with the OR is shown. At low and ...
