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Mette M Rosenkilde – One of the best experts on this subject based on the ideXlab platform.

  • The future of antiviral immunotoxins.
    Journal of leukocyte biology, 2016
    Co-Authors: Katja Spiess, Mette Høy Jakobsen, Thomas N. Kledal, Mette M Rosenkilde
    Abstract:

    There is a constant need for new therapeutic interventions in a wide range of infectious diseases. Over the past few years, the immunotoxins have entered the stage as promising antiviral treatments. Immunotoxins have been extensively explored in cancer treatment and have achieved FDA approval in several cases. Indeed, the design of new anticancer immunotoxins is a rapidly developing field. However, at present, several immunotoxins have been developed targeting a variety of different viruses with high specificity and efficacy. Rather than blocking a viral or cellular pathway needed for virus replication and dissemination, immunotoxins exert their effect by killing and eradicating the pool of infected cells. By targeting a virus-encoded target molecule, it is possible to obtain superior selectivity and drastically limit the side effects, which is an immunotoxin-related challenge that has hindered the success of immunotoxins in cancer treatment. Therefore, it seems beneficial to use immunotoxins for the treatment of virus infections. One recent example showed that targeting of virus-encoded 7 transmembrane (7TM) Receptors by immunotoxins could be a future strategy for designing ultraspecific antiviral treatment, ensuring efficient internalization and hence efficient eradication of the pool of infected cells, both in vitro and in vivo. In this review, we provide an overview of the mechanisms of action of immunotoxins and highlight the advantages of immunotoxins as future anti-viral therapies.

  • EBV,the HumanHost,andthe7TM Receptors: Defense or Offense?
    , 2015
    Co-Authors: Kristine Niss Arfelt, Suzan Fares, Mette M Rosenkilde
    Abstract:

    Being present in around 90% of the worldwide population, Epstein–Barr virus (EBV) is an exceptionally prevalent virus. This highly successful virus establishes a latent infection in resting memory B cells and is maintained in a balance between viral homeostasis on one side and antiviral defense of the immune system on the other side. The life cycle of EBV is dependent on many viral protproteins, but EBV also regulates a number of endogenous proteins. 7TM Receptors and ligands of viral and host origin are examples of such

  • EBV, the human host, and the 7TM Receptors: defense or offense?
    Progress in molecular biology and translational science, 2014
    Co-Authors: Kristine Niss Arfelt, Suzan Fares, Mette M Rosenkilde
    Abstract:

    Abstract Being present in around 90% of the worldwide population, Epstein–Barr virus (EBV) is an exceptionally prevalent virus. This highly successful virus establishes a latent infection in resting memory B cells and is maintained in a balance between viral homeostasis on one side and antiviral defense of the immune system on the other side. The life cycle of EBV is dependent on many viral protproteins, but EBV also regulates a number of endogenous proteins. 7TM Receptors and ligands of viral and host origin are examples of such proteins. 7TM Receptors are highly druggable and they are among the most popular class of investigational drug targets. The 7TM receptor encoded by EBV-BILF1, is known to downregulate cell surface MHC class I expression as part of the immune evasion strategy of EBV. However, the functional impact of the relationship between EBV and the regulated endogenous 7TM Receptors and ligands is still unclear. This is for instance the case for the most upregulated 7TM receptor EBI2 (EBV-induced gene 2 or GPR183). Whereas some regulated genes have been suggested to be involved in the EBV life cycle, others could also be important for the antiviral immune defense. As many of these 7TM Receptors and ligands have been shown to be modulated in EBV-associated diseases, targeting these could provide an efficient and specific way to inhibit EBV-associated disease progprogression. Here, we will review current knowledge on EBV infection, the immune defense against EBV and 7TM Receptors and ligands being either encoded or manipulated by EBV.

Thue W. Schwartz – One of the best experts on this subject based on the ideXlab platform.

  • In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist.
    Molecular informatics, 2015
    Co-Authors: Michael Lückmann, Birgitte Holst, Thue W. Schwartz, Thomas M Frimurer
    Abstract:

    The neurotensin receptor 1 (NTSR1) belongs to the family of 7TM, G protprotein-coupled Receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS) that has been shown to play important roles in neurological disorders and the promotion of cancer cells. Recently, a high-resolution x-ray crystal structure of NTSR1 in complex with NTS8-13 has been determined, providing novel insights into peptide ligand recognition by 7TM Receptors. SR48692, a potent and selective small molecule antagonist has previously been used extensively as a tool compound to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small molecule compounds to NTSR1, we applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. Structurally overlapping binding poses for SR48692 and NTS8-13 were observed, despite their distinct chemical nature and inverse pharmacological profiles. The optimized models showed significantly improved ligand recognition in a large-scale virtual screening assessment compared to the crystal structure. Our models provide new insights into small molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer.

  • The minor binding pocket: a major player in 7TM receptor activation.
    Trends in pharmacological sciences, 2010
    Co-Authors: Mette M Rosenkilde, Thomas M Frimurer, Tau Benned-jensen, Thue W. Schwartz
    Abstract:

    From the deep part of the main ligand-binding crevice, a minor, often shallower pocket extends between the extracellular ends of transmembrane domains (TM)-I, II, III and VII of 7TM Receptors. This minor binding pocket is defined by a highly conserved kink in TM-II that is induced by a proline resiresidue located in one of two adjacent positions. Here we argue that this minor binding pocket is important for receptor activation. Functional coupling of the Receptors seems to be mediated through the hydrogen bond network located between the intracellular segments of these TMs, with the allosteric interface between TM-II and TM-VII being of particular significance. Importantly, the minor binding pocket, especially the proline-kink in TM-II, is involved in G protprotein versus arrestin pathway-biased signaling, for example in the angiotensin AT1 system. Consequently, this pocket could be specifically targeted in the development of functionally biased drugs.

  • Conserved Water-mediated Hydrogen Bond Network between TM-I, -II, -VI, and -VII in 7TM Receptor Activation
    The Journal of biological chemistry, 2010
    Co-Authors: Rie Nygaard, Thomas M Frimurer, Louise Valentin-hansen, Jacek Mokrosinski, Thue W. Schwartz
    Abstract:

    Five highly conserved polar residues connected by a number of structural water molecules together with two rotamer micro-switches, TrpVI:13 and TyrVII:20, constitute an extended hydrogen bond network between the intracellular segments of TM-I, -II, -VI, and -VII of 7TM Receptors. Molecular dynamics simulations showed that, although the fewer water molecules in rhodopsin were relatively movable, the hydrogen bond network of the β2-adrenergic receptor was fully loaded with water molecules that were surprisingly immobilized between the two rotamer switches, both apparently being in their closed conformation. Manipulations of the rotamer state of TyrVII:20 and TrpVI:13 demonstrated that these residues served as gates for the water molecules at the intracellular and extracellular ends of the hydrogen bond network, respectively. TrpVI:13 at the bottom of the main ligand-binding pocket was shown to apparently function as a catching trap for water molecules. Mutational analysis of the β2-adrenergic receptor demonstrated that the highly conserved polar residues of the hydrogen bond network were all important for receptor signaling but served different functions, some dampening constitutive activity (AsnI:18, AspII:10, and AsnVII:13), whereas others (AsnVII:12 and AsnVII:16) located one helical turn apart and sharing a water molecule were shown to be essential for agonist-induced signaling. It is concluded that the conserved water hydrogen bond network of 7TM Receptors constitutes an extended allosteric interface between the transmembrane segments being of crucial importance for receptor signaling and that part of the function of the rotamer micro-switches, TyrVII:20 and TrpVI:13, is to gate or trap the water molecules.

Thomas M Frimurer – One of the best experts on this subject based on the ideXlab platform.

  • In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist.
    Molecular informatics, 2015
    Co-Authors: Michael Lückmann, Birgitte Holst, Thue W. Schwartz, Thomas M Frimurer
    Abstract:

    The neurotensin receptor 1 (NTSR1) belongs to the family of 7TM, G protein-coupled Receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS) that has been shown to play important roles in neurological disorders and the promotion of cancer cells. Recently, a high-resolution x-ray crystal structure of NTSR1 in complex with NTS8-13 has been determined, providing novel insights into peptide ligand recognition by 7TM Receptors. SR48692, a potent and selective small molecule antagonist has previously been used extensively as a tool compound to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small molecule compounds to NTSR1, we applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. Structurally overlapping binding poses for SR48692 and NTS8-13 were observed, despite their distinct chemical nature and inverse pharmacological profiles. The optimized models showed significantly improved ligand recognition in a large-scale virtual screening assessment compared to the crystal structure. Our models provide new insights into small molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer.

  • Gating function of isoleucine-116 in TM-3 (position III:16/3.40) for the activity state of the CC-chemokine receptor 5 (CCR5).
    British journal of pharmacology, 2014
    Co-Authors: Anne Steen, Thomas M Frimurer, Alexander Hovard Sparre-ulrich, Stefanie Thiele, Dong Guo, Mette M Rosenkilde
    Abstract:

    Background and Purpose A conserved amino acid within a protein family indicates a significance of the residue. In the centre of transmembrane helix (TM)-5, position V:13/5.47, an aromatic aminamino acid is conserved among class A 7TM Receptors. However, in 37% of chemokine Receptors – a subgroup of 7TM Receptors – it is a leucine indicating an altered function. Here, we describe the significance of this position and its possible interaction with TM-3 for CCR5 activity. Experimental Approach The effects of [L203F]-CCR5 in TM-5 (position V:13/5.47), [I116A]-CCR5 in TM-3 (III:16/3.40) and [L203F;G286F]-CCR5 (V:13/5.47;VII:09/7.42) were determined in G-protein– and β-arrestin-coupled signalling. Computational modelling monitored changes in amino acid conformation. Key Results [L203F]-CCR5 increased the basal level of G-protein coupling (20–70% of Emax) and β-arrestin recruitment (50% of Emax) with a threefold increase in agonist potency. In silico, [I116A]-CCR5 switched χ1-angle in [L203F]-CCR5. Furthermore, [I116A]-CCR5 was constitutively active to a similar degree as [L203F]-CCR5. Tyr244 in TM-6 (VI:09/6.44) moved towards TM-5 in silico, consistent with its previously shown function for CCR5 activation. On [L203F;G286F]-CCR5 the antagonist aplaviroc was converted to a superagonist. Conclusions and Implications The results imply that an aromatic aminamino acid in the centre of TM-5 controls the level of receptor activity. Furthermore, Ile116 acts as a gate for the movement of Tyr244 towards TM-5 in the active state, a mechanism proposed previously for the β2-adrenoceptor. The results provide an understanding of chemokine receptor function and thereby information for the development of biased and non-biased antagonists and inverse agonists.

  • Biased and constitutive signaling in the CC-chemokine receptor CCR5 by manipulating the interface between transmembrane helices 6 and 7.
    The Journal of biological chemistry, 2013
    Co-Authors: Anne Steen, Thomas M Frimurer, Stefanie Thiele, Dong Guo, L S Hansen, Mette M Rosenkilde
    Abstract:

    The equilibrium state of CCR5 is manipulated here toward either activation or inactivation by introduction of single amino acid substitutions in the transmembrane domains (TMs) 6 and 7. Insertion of a steric hindrance mutation in the center of TM7 (G286F in position VII:09/7.42) resulted in biased signaling. Thus, β-arrestin recruitment was eliminated, whereas constitutive activity was observed in Gαi-mediated signaling. Furthermore, the CCR5 antagonist aplaviroc was converted to a full agonist (a so-called efficacy switch). Computational modeling revealed that the position of the 7TM receptor-conserved Trp in TM6 (Trp-248 in position VI:13/6.48, part of the CWXP motif) was influenced by the G286F mutation, causing Trp-248 to change orientation away from TM7. The essential role of Trp-248 in CCR5 activation was supported by complete inactivity of W248A-CCR5 despite maintaining chemokine binding. Furthermore, replacing Trp-248 with a smaller aromatic aminamino acid (Tyr/Phe) impaired the β-arrestin recruitment, yet with maintained G protprotein activity (biased signaling); also, here aplaviroc switched to a full agonist. Thus, the altered positioning of Trp-248, induced by G286F, led to a constraint of G protprotein active, but β-arrestin inactive and thus biased, CCR5 conformation. These results provide important information on the molecular interplay and impact of TM6 and TM7 for CCR5 activity, which may be extrapolated to other chemokine Receptors and possibly to other 7TM Receptors.

Birgitte Holst – One of the best experts on this subject based on the ideXlab platform.

  • In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist.
    Molecular informatics, 2015
    Co-Authors: Michael Lückmann, Birgitte Holst, Thue W. Schwartz, Thomas M Frimurer
    Abstract:

    The neurotensin receptor 1 (NTSR1) belongs to the family of 7TM, G protein-coupled Receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS) that has been shown to play important roles in neurological disorders and the promotion of cancer cells. Recently, a high-resolution x-ray crystal structure of NTSR1 in complex with NTS8-13 has been determined, providing novel insights into peptide ligand recognition by 7TM Receptors. SR48692, a potent and selective small molecule antagonist has previously been used extensively as a tool compound to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small molecule compounds to NTSR1, we applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. Structurally overlapping binding poses for SR48692 and NTS8-13 were observed, despite their distinct chemical nature and inverse pharmacological profiles. The optimized models showed significantly improved ligand recognition in a large-scale virtual screening assessment compared to the crystal structure. Our models provide new insights into small molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer.

  • functionally biased signalling properties of 7TM Receptors opportunities for drug development for the ghrelin receptor
    British Journal of Pharmacology, 2013
    Co-Authors: Bjørn Sivertsen, Nicholas D. Holliday, Andreas N. Madsen, Birgitte Holst
    Abstract:

    The ghrelin receptor is a 7 transmembrane (7TM) receptor involved in a variety of physiological functions including growth hormone secretion, increased food intake and fat accumulation as well as modulation of reward and cognitive functions. Because of its important role in metabolism and energy expenditure, the ghrelin receptor has become an important therapeutic target for drug design and the development of anti-obesity compounds. However, none of the compounds developed so far have been approved for commercial use. Interestingly, the ghrelin receptor is able to signal through several different signalling pathways including Gαq, Gαi/o, Gα12/13 and arrestin recruitment. These multiple signalling pathways allow for functionally biased signalling, where one signalling pathway may be favoured over another either by selective ligands or through mutations in the receptor. In the present review, we have described how ligands and mutations in the 7TM receptor may bias the Receptors to favour either one G-protein over another or to promote G-protein independent signalling pathways rather than G–protein-dependent pathways. For the ghrelin receptor, both agonist and inverse agonists have been demonstrated to signal more strongly through the Gαq-coupled pathway than the Gα12/13-coupled pathway. Similarly a ligand that promotes Gαq coupling over Gαi coupling has been described and it has been suggested that several different active conformations of the receptor may exist dependent on the properties of the agonist. Importantly, ligands with such biased signalling properties may allow the development of drugs that selectively modulate only the therapeutically relevant physiological functions, thereby decreasing the risk of side effects. Linked Articles This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7

  • Functionally biased signalling properties of 7TM Receptors – opportunities for drug development for the ghrelin receptor
    British journal of pharmacology, 2013
    Co-Authors: Bjørn Sivertsen, Nicholas D. Holliday, Andreas N. Madsen, Birgitte Holst
    Abstract:

    The ghrelin receptor is a 7 transmembrane (7TM) receptor involved in a variety of physiological functions including growth hormone secretion, increased food intake and fat accumulation as well as modulation of reward and cognitive functions. Because of its important role in metabolism and energy expenditure, the ghrelin receptor has become an important therapeutic target for drug design and the development of anti-obesity compounds. However, none of the compounds developed so far have been approved for commercial use. Interestingly, the ghrelin receptor is able to signal through several different signalling pathways including Gαq, Gαi/o, Gα12/13 and arrestin recruitment. These multiple signalling pathways allow for functionally biased signalling, where one signalling pathway may be favoured over another either by selective ligands or through mutations in the receptor. In the present review, we have described how ligands and mutations in the 7TM receptor may bias the Receptors to favour either one G-protein over another or to promote G-protein independent signalling pathways rather than G–protein-dependent pathways. For the ghrelin receptor, both agonist and inverse agonists have been demonstrated to signal more strongly through the Gαq-coupled pathway than the Gα12/13-coupled pathway. Similarly a ligand that promotes Gαq coupling over Gαi coupling has been described and it has been suggested that several different active conformations of the receptor may exist dependent on the properties of the agonist. Importantly, ligands with such biased signalling properties may allow the development of drugs that selectively modulate only the therapeutically relevant physiological functions, thereby decreasing the risk of side effects. Linked Articles This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7

Christian E. Elling – One of the best experts on this subject based on the ideXlab platform.

  • Construction of covalently coupled, concatameric dimers of 7TM Receptors.
    Journal of receptor and signal transduction research, 2009
    Co-Authors: Marie Terpager, Christian E. Elling, D. Jason Scholl, Valentina Kubale, Lene Martini, Thue W. Schwartz
    Abstract:

    7TM Receptors are easily fused to proteins such as G protproteins and arrestin but because of the fact that their terminals are found on each side of the membrane they cannot be joined directly in covalent dimers. Here, we use an artificial connector comprising a transmembrane helix composed of Leu-Ala repeats flanked by flexible spacers and positively charged residues to ensure correct inside-out orientation plus an extracellular HA-tag to construct covalently coupled dimers of 7TM Receptors. Such 15 TM concatameric homo- and heterodimers of the β2-adrenergic and the NK1 Receptors, which normally do not dimerize with each other, were expressed surprisingly well at the cell surface, where they bound ligands and activated signal transduction in a manner rather similar to the corresponding wild-type Receptors. The concatameric heterodimers internalized upon stimulation with agonists for either of the protomers, which was not observed upon simple coexpression of the two Receptors. It is concluded that covalently…

  • Metal Ion Site Engineering Indicates a Global Toggle Switch Model for Seven-transmembrane Receptor Activation
    The Journal of biological chemistry, 2006
    Co-Authors: Christian E. Elling, Thomas M Frimurer, Birgitte Holst, Rasmus Jorgensen, Lars-ole Gerlach, Thue W. Schwartz
    Abstract:

    Much evidence indicates that, during activation of seven-transmembrane (7TM) Receptors, the intracellular segments of the transmembrane helices (TMs) move apart with large amplitude, rigid body movements of especially TM-VI and TM-VII. In this study, AspIII:08 (Asp113), the anchor point for monoamine binding in TM-III, was used as the starting point to engineer activating metal ion sites between the extracellular segments of the beta2-adrenergic receptor. Cu(II) and Zn(II) alone and in complex with aromatic chelators acted as potent (EC50 decreased to 0.5 microm) and efficacious agonists in sites constructed between positions III:08 (Asp or His), VI:16 (preferentially Cys), and/or VII:06 (preferentially Cys). In molecular models built over the backbone conformation of the inactive rhodopsin structure, the heavy atoms that coordinate the metal ion were located too far away from each other to form high affinity metal ion sites in both the bidentate and potential tridentate settings. This indicates that the residues involved in the main ligand-binding pocket will have to move closer to each other during receptor activation. On the basis of the distance constraints from these activating metal ion sites, we propose a global toggle switch mechanism for 7TM receptor activation in which inward movement of the extracellular segments of especially TM-VI and, to some extent, TM-VII is coupled to the well established outward movement of the intracellular segments of these helices. We suggest that the pivots for these vertical seesaw movements are the highly conserved proline bends of the involved helices.

  • molecular mechanism of 7TM receptor activation a global toggle switch model
    Annual Review of Pharmacology and Toxicology, 2006
    Co-Authors: Thue W. Schwartz, Mette M Rosenkilde, Thomas M Frimurer, Birgitte Holst, Christian E. Elling
    Abstract:

    The multitude of chemically highly different agonists for 7TM Receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VI-and to some degree TM-VII-around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.