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Ben Tehan - One of the best experts on this subject based on the ideXlab platform.

  • fragment and struCture based drug disCovery for a Class C gpCr disCovery of the mglu5 negative allosteriC modulator htl14242 3 Chloro 5 6 5 fluoropyridin 2 yl pyrimidin 4 yl benzonitrile
    Journal of Medicinal Chemistry, 2015
    Co-Authors: John A Christopher, A S Dore, K Okrasa, Maria Josefa Serranovega, Sarah Joanne Aves, K A Bennett, J C Errey, A Jazayeri, Fiona H Marshall, Ben Tehan
    Abstract:

    Fragment sCreening of a thermostabilized mGlu5 reCeptor using a high-ConCentration radioligand binding assay enabled the identifiCation of moderate affinity, high ligand effiCienCy (LE) pyrimidine hit 5. Subsequent optimization using struCture-based drug disCovery methods led to the seleCtion of 25, HTL14242, as an advanCed lead Compound for further development. StruCtures of the stabilized mGlu5 reCeptor Complexed with 25 and another moleCule in the series, 14, were determined at resolutions of 2.6 and 3.1 A, respeCtively.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, Samir Khan, J C Patel, Allahyar Jazayeri, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders. An X-ray struCture is presented for metabotropiC glutamate reCeptor 5, a Class C G-protein-Coupled glutamate reCeptor linked to fragile X syndrome and neurologiCal disorders; this study provides insights into the protein’s meChanism of aCtion. This manusCript presents the X-ray Crystal struCture of the transmembrane portion of the metabotropiC glutamate reCeptor 5 (mGlu5), a Class C G-protein-Coupled reCeptor (GPCR), in the presenCe of mavoglurant, a negative allosteriC modulator. Negative allosteriC modulators of mGlu5 are in CliniCal trials for the treatment of fragile X syndrome, depression, anxiety, migraine and dyskinesias; positive allosteriC modulators of mGlu5 might be useful for the treatment of sChizophrenia and Cognitive disorders. In this struCture, mavoglurant is found in a poCket that is about 8 A from the extraCellular reCeptor surfaCe.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, J C Patel, Ali Jazayeri, Samir A Khan, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders.

A S Dore - One of the best experts on this subject based on the ideXlab platform.

  • fragment and struCture based drug disCovery for a Class C gpCr disCovery of the mglu5 negative allosteriC modulator htl14242 3 Chloro 5 6 5 fluoropyridin 2 yl pyrimidin 4 yl benzonitrile
    Journal of Medicinal Chemistry, 2015
    Co-Authors: John A Christopher, A S Dore, K Okrasa, Maria Josefa Serranovega, Sarah Joanne Aves, K A Bennett, J C Errey, A Jazayeri, Fiona H Marshall, Ben Tehan
    Abstract:

    Fragment sCreening of a thermostabilized mGlu5 reCeptor using a high-ConCentration radioligand binding assay enabled the identifiCation of moderate affinity, high ligand effiCienCy (LE) pyrimidine hit 5. Subsequent optimization using struCture-based drug disCovery methods led to the seleCtion of 25, HTL14242, as an advanCed lead Compound for further development. StruCtures of the stabilized mGlu5 reCeptor Complexed with 25 and another moleCule in the series, 14, were determined at resolutions of 2.6 and 3.1 A, respeCtively.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, Samir Khan, J C Patel, Allahyar Jazayeri, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders. An X-ray struCture is presented for metabotropiC glutamate reCeptor 5, a Class C G-protein-Coupled glutamate reCeptor linked to fragile X syndrome and neurologiCal disorders; this study provides insights into the protein’s meChanism of aCtion. This manusCript presents the X-ray Crystal struCture of the transmembrane portion of the metabotropiC glutamate reCeptor 5 (mGlu5), a Class C G-protein-Coupled reCeptor (GPCR), in the presenCe of mavoglurant, a negative allosteriC modulator. Negative allosteriC modulators of mGlu5 are in CliniCal trials for the treatment of fragile X syndrome, depression, anxiety, migraine and dyskinesias; positive allosteriC modulators of mGlu5 might be useful for the treatment of sChizophrenia and Cognitive disorders. In this struCture, mavoglurant is found in a poCket that is about 8 A from the extraCellular reCeptor surfaCe.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, J C Patel, Ali Jazayeri, Samir A Khan, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders.

Maria Josefa Serranovega - One of the best experts on this subject based on the ideXlab platform.

  • fragment and struCture based drug disCovery for a Class C gpCr disCovery of the mglu5 negative allosteriC modulator htl14242 3 Chloro 5 6 5 fluoropyridin 2 yl pyrimidin 4 yl benzonitrile
    Journal of Medicinal Chemistry, 2015
    Co-Authors: John A Christopher, A S Dore, K Okrasa, Maria Josefa Serranovega, Sarah Joanne Aves, K A Bennett, J C Errey, A Jazayeri, Fiona H Marshall, Ben Tehan
    Abstract:

    Fragment sCreening of a thermostabilized mGlu5 reCeptor using a high-ConCentration radioligand binding assay enabled the identifiCation of moderate affinity, high ligand effiCienCy (LE) pyrimidine hit 5. Subsequent optimization using struCture-based drug disCovery methods led to the seleCtion of 25, HTL14242, as an advanCed lead Compound for further development. StruCtures of the stabilized mGlu5 reCeptor Complexed with 25 and another moleCule in the series, 14, were determined at resolutions of 2.6 and 3.1 A, respeCtively.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, Samir Khan, J C Patel, Allahyar Jazayeri, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders. An X-ray struCture is presented for metabotropiC glutamate reCeptor 5, a Class C G-protein-Coupled glutamate reCeptor linked to fragile X syndrome and neurologiCal disorders; this study provides insights into the protein’s meChanism of aCtion. This manusCript presents the X-ray Crystal struCture of the transmembrane portion of the metabotropiC glutamate reCeptor 5 (mGlu5), a Class C G-protein-Coupled reCeptor (GPCR), in the presenCe of mavoglurant, a negative allosteriC modulator. Negative allosteriC modulators of mGlu5 are in CliniCal trials for the treatment of fragile X syndrome, depression, anxiety, migraine and dyskinesias; positive allosteriC modulators of mGlu5 might be useful for the treatment of sChizophrenia and Cognitive disorders. In this struCture, mavoglurant is found in a poCket that is about 8 A from the extraCellular reCeptor surfaCe.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, J C Patel, Ali Jazayeri, Samir A Khan, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders.

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

  • fragment and struCture based drug disCovery for a Class C gpCr disCovery of the mglu5 negative allosteriC modulator htl14242 3 Chloro 5 6 5 fluoropyridin 2 yl pyrimidin 4 yl benzonitrile
    Journal of Medicinal Chemistry, 2015
    Co-Authors: John A Christopher, A S Dore, K Okrasa, Maria Josefa Serranovega, Sarah Joanne Aves, K A Bennett, J C Errey, A Jazayeri, Fiona H Marshall, Ben Tehan
    Abstract:

    Fragment sCreening of a thermostabilized mGlu5 reCeptor using a high-ConCentration radioligand binding assay enabled the identifiCation of moderate affinity, high ligand effiCienCy (LE) pyrimidine hit 5. Subsequent optimization using struCture-based drug disCovery methods led to the seleCtion of 25, HTL14242, as an advanCed lead Compound for further development. StruCtures of the stabilized mGlu5 reCeptor Complexed with 25 and another moleCule in the series, 14, were determined at resolutions of 2.6 and 3.1 A, respeCtively.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, Samir Khan, J C Patel, Allahyar Jazayeri, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders. An X-ray struCture is presented for metabotropiC glutamate reCeptor 5, a Class C G-protein-Coupled glutamate reCeptor linked to fragile X syndrome and neurologiCal disorders; this study provides insights into the protein’s meChanism of aCtion. This manusCript presents the X-ray Crystal struCture of the transmembrane portion of the metabotropiC glutamate reCeptor 5 (mGlu5), a Class C G-protein-Coupled reCeptor (GPCR), in the presenCe of mavoglurant, a negative allosteriC modulator. Negative allosteriC modulators of mGlu5 are in CliniCal trials for the treatment of fragile X syndrome, depression, anxiety, migraine and dyskinesias; positive allosteriC modulators of mGlu5 might be useful for the treatment of sChizophrenia and Cognitive disorders. In this struCture, mavoglurant is found in a poCket that is about 8 A from the extraCellular reCeptor surfaCe.

  • struCture of Class C gpCr metabotropiC glutamate reCeptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, J C Patel, Ali Jazayeri, Samir A Khan, Ben Tehan
    Abstract:

    MetabotropiC glutamate reCeptors are Class C G-protein-Coupled reCeptors whiCh respond to the neurotransmitter glutamate. StruCtural studies have been restriCted to the amino-terminal extraCellular domain, providing little understanding of the membrane-spanning signal transduCtion domain. MetabotropiC glutamate reCeptor 5 is of Considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiCtion and movement disorders. Here we report the Crystal struCture of the transmembrane domain of the human reCeptor in Complex with the negative allosteriC modulator, mavoglurant. The struCture provides detailed insight into the arChiteCture of the transmembrane domain of Class C reCeptors inCluding the preCise loCation of the allosteriC binding site within the transmembrane domain and key miCro-switChes whiCh regulate reCeptor signalling. This struCture also provides a model for all Class C G-protein-Coupled reCeptors and may aid in the design of new small-moleCule drugs for the treatment of brain disorders.

Aylin C Hanyaloglu - One of the best experts on this subject based on the ideXlab platform.

  • ap2σ mutations impair CalCium sensing reCeptor traffiCking and signaling and show an endosomal pathway to spatially direCt g protein seleCtivity
    Cell Reports, 2018
    Co-Authors: Caroline M Gorvin, Angela Rogers, Benoit Hastoy, Andrei I Tarasov, Morten Frost, Silvia Sposini, Asuka Inoue, Michael P Whyte, Patrik Rorsman, Aylin C Hanyaloglu
    Abstract:

    Summary Spatial Control of G-protein-Coupled reCeptor (GPCR) signaling, whiCh is used by Cells to translate Complex information into distinCt downstream responses, is aChieved by using plasma membrane (PM) and endoCytiC-derived signaling pathways. The roles of the endomembrane in regulating suCh pleiotropiC signaling via multiple G-protein pathways remain unknown. Here, we investigated the effeCts of disease-Causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the Class C GPCR CalCium-sensing reCeptor (CaSR). These AP2σ mutations inCrease CaSR PM expression yet paradoxiCally reduCe CaSR signaling. HyperCalCemia-assoCiated AP2σ mutations reduCed CaSR signaling via Gαq/11 and Gαi/o pathways. The mutations also delayed CaSR internalization due to prolonged residenCy time of CaSR in Clathrin struCtures that impaired or abolished endosomal signaling, whiCh was predominantly mediated by Gαq/11. Thus, Compartmental bias for CaSR-mediated Gαq/11 endomembrane signaling provides a meChanistiC basis for multidimensional GPCR signaling.

  • AP2σ mutations impair CalCium-sensing reCeptor traffiCking and signaling, and reveal an endosomal pathway that spatially-direCts G-protein seleCtivity
    'Elsevier BV', 2018
    Co-Authors: Caroline M Gorvin, Rogers A, Hastoy B, Ai Tarasov, Frost M, Sposini S, Inoue A, Whyte M, Rorsman P, Aylin C Hanyaloglu
    Abstract:

    Spatial Control of G-protein-Coupled reCeptor (GPCR) signaling, whiCh is used by Cells to translate Complex information into distinCt downstream responses, is aChieved by using plasma membrane (PM) and endoCytiC-derived signaling pathways. The roles of the endomembrane in regulating suCh pleiotropiC signaling via multiple G-protein pathways remain unknown. Here, we investigated the effeCts of disease-Causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the Class C GPCR CalCium-sensing reCeptor (CaSR). These AP2σ mutations inCrease CaSR PM expression yet paradoxiCally reduCe CaSR signaling. HyperCalCemia-assoCiated AP2σ mutations reduCed CaSR signaling via Gαq/11 and Gαi/o pathways. The mutations also delayed CaSR internalization due to prolonged residenCy time of CaSR in Clathrin struCtures that impaired or abolished endosomal signaling, whiCh was predominantly mediated by Gαq/11. Thus, Compartmental bias for CaSR-mediated Gαq/11 endomembrane signaling provides a meChanistiC basis for multidimensional GPCR signaling