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  • 1
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    Propagation of conformational changes during mu-opioid receptor activation (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-08-08
    Description: micro-Opioid receptors (microORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the muOR in inactive and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of muOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the muOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the beta2-adrenergic receptor. Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sounier, Remy -- Mas, Camille -- Steyaert, Jan -- Laeremans, Toon -- Manglik, Aashish -- Huang, Weijiao -- Kobilka, Brian K -- Demene, Helene -- Granier, Sebastien -- DA036246/DA/NIDA NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):375-8. doi: 10.1038/nature14680. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Centre de Biochimie Structurale, CNRS UMR 5048-INSERM 1054- University of Montpellier, 29 rue de Navacelles, 34090 Montpellier Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245377" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Binding Sites ; Heterotrimeric GTP-Binding Proteins/metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Morphinans/chemistry/metabolism/pharmacology ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation/drug effects ; Pyrroles/chemistry/metabolism/pharmacology ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Opioid, mu/*chemistry/*metabolism ; Single-Chain Antibodies/chemistry/metabolism/pharmacology ; Structure-Activity Relationship ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-01-14
    Description: G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human beta(2) adrenergic receptor (beta(2)AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive beta(2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11 A outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058308/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058308/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rasmussen, Soren G F -- Choi, Hee-Jung -- Fung, Juan Jose -- Pardon, Els -- Casarosa, Paola -- Chae, Pil Seok -- Devree, Brian T -- Rosenbaum, Daniel M -- Thian, Foon Sun -- Kobilka, Tong Sun -- Schnapp, Andreas -- Konetzki, Ingo -- Sunahara, Roger K -- Gellman, Samuel H -- Pautsch, Alexander -- Steyaert, Jan -- Weis, William I -- Kobilka, Brian K -- GM083118/GM/NIGMS NIH HHS/ -- GM56169/GM/NIGMS NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- P01 GM75913/GM/NIGMS NIH HHS/ -- P60DK-20572/DK/NIDDK NIH HHS/ -- R01 GM068603/GM/NIGMS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 GM083118-04/GM/NIGMS NIH HHS/ -- R37 NS028471/NS/NINDS NIH HHS/ -- R37 NS028471-21/NS/NINDS NIH HHS/ -- England -- Nature. 2011 Jan 13;469(7329):175-80. doi: 10.1038/nature09648.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21228869" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor ; Agonists/*chemistry/immunology/metabolism/*pharmacology ; Animals ; Binding Sites ; Camelids, New World ; Crystallography, X-Ray ; Drug Inverse Agonism ; Humans ; Immunoglobulin Fragments/*chemistry/*immunology/metabolism/pharmacology ; Ligands ; Models, Molecular ; Movement/drug effects ; Nanostructures/*chemistry ; Opsins/agonists/chemistry/metabolism ; Propanolamines/chemistry/metabolism/pharmacology ; Protein Conformation/drug effects ; Protein Stability/drug effects ; Receptors, Adrenergic, beta-2/*chemistry/*metabolism ; Viral Proteins/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Activation and allosteric modulation of a muscarinic acetylcholine receptor (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-22
    Description: Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the beta2 adrenergic receptor (beta2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the beta2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020789/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kruse, Andrew C -- Ring, Aaron M -- Manglik, Aashish -- Hu, Jianxin -- Hu, Kelly -- Eitel, Katrin -- Hubner, Harald -- Pardon, Els -- Valant, Celine -- Sexton, Patrick M -- Christopoulos, Arthur -- Felder, Christian C -- Gmeiner, Peter -- Steyaert, Jan -- Weis, William I -- Garcia, K Christopher -- Wess, Jurgen -- Kobilka, Brian K -- GM08311806/GM/NIGMS NIH HHS/ -- NS02847123/NS/NINDS NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- U19 GM106990/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Dec 5;504(7478):101-6. doi: 10.1038/nature12735. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256733" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Binding Sites ; Cytoplasm/metabolism ; Humans ; Isoxazoles/chemistry/metabolism ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Quaternary Ammonium Compounds/chemistry/metabolism ; Receptors, Muscarinic/*chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Structural insights into micro-opioid receptor activation (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-08-08
    Description: Activation of the mu-opioid receptor (muOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for muOR activation, here we report a 2.1 A X-ray crystal structure of the murine muOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the muOR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta2-adrenergic receptor (beta2AR) and the M2 muscarinic receptor. Comparison with active beta2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the muOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Weijiao -- Manglik, Aashish -- Venkatakrishnan, A J -- Laeremans, Toon -- Feinberg, Evan N -- Sanborn, Adrian L -- Kato, Hideaki E -- Livingston, Kathryn E -- Thorsen, Thor S -- Kling, Ralf C -- Granier, Sebastien -- Gmeiner, Peter -- Husbands, Stephen M -- Traynor, John R -- Weis, William I -- Steyaert, Jan -- Dror, Ron O -- Kobilka, Brian K -- R01GM083118/GM/NIGMS NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- R37DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):315-21. doi: 10.1038/nature14886. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA. ; Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany. ; Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. ; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245379" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Binding Sites ; Crystallography, X-Ray ; Heterotrimeric GTP-Binding Proteins/chemistry/metabolism ; Mice ; Models, Molecular ; Molecular Dynamics Simulation ; Morphinans/chemistry/metabolism/pharmacology ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Pyrroles/chemistry/metabolism/pharmacology ; Receptor, Muscarinic M2/chemistry ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Opioid, mu/agonists/*chemistry/*metabolism ; Single-Chain Antibodies/chemistry/pharmacology ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Crystal structure of the beta2 adrenergic receptor-Gs protein complex (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-21
    Description: G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The beta(2) adrenergic receptor (beta(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric beta(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the beta(2)AR and Gs involve the amino- and carboxy-terminal alpha-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the beta(2)AR include a 14 A outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an alpha-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the alpha-helical domain of Galphas relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184188/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184188/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rasmussen, Soren G F -- DeVree, Brian T -- Zou, Yaozhong -- Kruse, Andrew C -- Chung, Ka Young -- Kobilka, Tong Sun -- Thian, Foon Sun -- Chae, Pil Seok -- Pardon, Els -- Calinski, Diane -- Mathiesen, Jesper M -- Shah, Syed T A -- Lyons, Joseph A -- Caffrey, Martin -- Gellman, Samuel H -- Steyaert, Jan -- Skiniotis, Georgios -- Weis, William I -- Sunahara, Roger K -- Kobilka, Brian K -- GM083118/GM/NIGMS NIH HHS/ -- GM56169/GM/NIGMS NIH HHS/ -- GM75915/GM/NIGMS NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- P01 GM75913/GM/NIGMS NIH HHS/ -- P50GM073210/GM/NIGMS NIH HHS/ -- P60DK-20572/DK/NIDDK NIH HHS/ -- R01 GM068603/GM/NIGMS NIH HHS/ -- R01 GM068603-01/GM/NIGMS NIH HHS/ -- R01 GM068603-02/GM/NIGMS NIH HHS/ -- R01 GM068603-03/GM/NIGMS NIH HHS/ -- R01 GM068603-04/GM/NIGMS NIH HHS/ -- R01 GM068603-05/GM/NIGMS NIH HHS/ -- T32-GM008270/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54GM094599/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jul 19;477(7366):549-55. doi: 10.1038/nature10361.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21772288" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor Agonists/chemistry/metabolism ; Animals ; Catalytic Domain ; Cattle ; Crystallization ; Crystallography, X-Ray ; Enzyme Activation ; GTP-Binding Protein alpha Subunits, Gs/*chemistry/*metabolism ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Protein Binding ; Rats ; Receptors, Adrenergic, beta-2/*chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    SbsB structure and lattice reconstruction unveil Ca2+ triggered S-layer assembly (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: S-layers are regular two-dimensional semipermeable protein layers that constitute a major cell-wall component in archaea and many bacteria. The nanoscale repeat structure of the S-layer lattices and their self-assembly from S-layer proteins (SLPs) have sparked interest in their use as patterning and display scaffolds for a range of nano-biotechnological applications. Despite their biological abundance and the technological interest in them, structural information about SLPs is limited to truncated and assembly-negative proteins. Here we report the X-ray structure of the SbsB SLP of Geobacillus stearothermophilus PV72/p2 by the use of nanobody-aided crystallization. SbsB consists of a seven-domain protein, formed by an amino-terminal cell-wall attachment domain and six consecutive immunoglobulin-like domains, that organize into a phi-shaped disk-like monomeric crystallization unit stabilized by interdomain Ca(2+) ion coordination. A Ca(2+)-dependent switch to the condensed SbsB quaternary structure pre-positions intermolecular contact zones and renders the protein competent for S-layer assembly. On the basis of crystal packing, chemical crosslinking data and cryo-electron microscopy projections, we present a model for the molecular organization of this SLP into a porous protein sheet inside the S-layer. The SbsB lattice represents a previously undescribed structural model for protein assemblies and may advance our understanding of SLP physiology and self-assembly, as well as the rational design of engineered higher-order structures for biotechnology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baranova, Ekaterina -- Fronzes, Remi -- Garcia-Pino, Abel -- Van Gerven, Nani -- Papapostolou, David -- Pehau-Arnaudet, Gerard -- Pardon, Els -- Steyaert, Jan -- Howorka, Stefan -- Remaut, Han -- BB/E010466/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2012 Jul 5;487(7405):119-22. doi: 10.1038/nature11155.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural and Molecular Microbiology, VIB Department of Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722836" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Calcium/chemistry/metabolism/*pharmacology ; Cryoelectron Microscopy ; Crystallization/methods ; Crystallography, X-Ray ; Geobacillus stearothermophilus/*chemistry ; Immunoglobulins/chemistry ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Nanostructures/chemistry ; Polymerization/drug effects ; Protein Structure, Quaternary/drug effects ; Protein Structure, Tertiary/drug effects ; Solutions
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Conformational biosensors reveal GPCR signalling from endosomes (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-22
    Description: A long-held tenet of molecular pharmacology is that canonical signal transduction mediated by G-protein-coupled receptor (GPCR) coupling to heterotrimeric G proteins is confined to the plasma membrane. Evidence supporting this traditional view is based on analytical methods that provide limited or no subcellular resolution. It has been subsequently proposed that signalling by internalized GPCRs is restricted to G-protein-independent mechanisms such as scaffolding by arrestins, or GPCR activation elicits a discrete form of persistent G protein signalling, or that internalized GPCRs can indeed contribute to the acute G-protein-mediated response. Evidence supporting these various latter hypotheses is indirect or subject to alternative interpretation, and it remains unknown if endosome-localized GPCRs are even present in an active form. Here we describe the application of conformation-specific single-domain antibodies (nanobodies) to directly probe activation of the beta2-adrenoceptor, a prototypical GPCR, and its cognate G protein, Gs (ref. 12), in living mammalian cells. We show that the adrenergic agonist isoprenaline promotes receptor and G protein activation in the plasma membrane as expected, but also in the early endosome membrane, and that internalized receptors contribute to the overall cellular cyclic AMP response within several minutes after agonist application. These findings provide direct support for the hypothesis that canonical GPCR signalling occurs from endosomes as well as the plasma membrane, and suggest a versatile strategy for probing dynamic conformational change in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835555/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835555/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Irannejad, Roshanak -- Tomshine, Jin C -- Tomshine, Jon R -- Chevalier, Michael -- Mahoney, Jacob P -- Steyaert, Jan -- Rasmussen, Soren G F -- Sunahara, Roger K -- El-Samad, Hana -- Huang, Bo -- von Zastrow, Mark -- DA010711/DA/NIDA NIH HHS/ -- DA012864/DA/NIDA NIH HHS/ -- F32 DA029993/DA/NIDA NIH HHS/ -- GM083118/GM/NIGMS NIH HHS/ -- P01 DA010154/DA/NIDA NIH HHS/ -- P01 NS053709/NS/NINDS NIH HHS/ -- R01 DA012864/DA/NIDA NIH HHS/ -- R01 GM068603/GM/NIGMS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R29 DA010711/DA/NIDA NIH HHS/ -- R37 DA010711/DA/NIDA NIH HHS/ -- T32 GM007767/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Mar 28;495(7442):534-8. doi: 10.1038/nature12000. Epub 2013 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23515162" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor Agonists/pharmacology ; Biosensing Techniques/*methods ; Cell Membrane/chemistry/metabolism ; Clathrin-Coated Vesicles ; Cyclic AMP/metabolism ; Endocytosis ; Endosomes/chemistry/*metabolism ; GTP-Binding Protein alpha Subunits, Gs/metabolism ; Green Fluorescent Proteins/analysis/genetics/metabolism ; HEK293 Cells ; Humans ; Isoproterenol/pharmacology ; Models, Biological ; Protein Conformation ; Receptors, Adrenergic, beta-2/*chemistry/immunology/*metabolism ; *Signal Transduction ; Single-Domain Antibodies/genetics/immunology
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  • 8
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    Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-10
    Description: Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis, and autophagy. We present the 4.4 angstrom crystal structure of the 385-kilodalton endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1), and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm, where the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity. Vps30 and Vps38 form the other arm that brackets the Vps15/Vps34 heterodimer, suggesting a path for complex assembly. We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to reveal conformational changes accompanying membrane binding and identify a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601532/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601532/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rostislavleva, Ksenia -- Soler, Nicolas -- Ohashi, Yohei -- Zhang, Lufei -- Pardon, Els -- Burke, John E -- Masson, Glenn R -- Johnson, Chris -- Steyaert, Jan -- Ktistakis, Nicholas T -- Williams, Roger L -- BB/K019155/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- PG11/109/29247/British Heart Foundation/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):aac7365. doi: 10.1126/science.aac7365.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ; Structural Biology Research Center, VIB, B-1050 Brussels, Belgium. Structural Biology Brussels, Vrije Universiteit Brussel, B-1050 Brussels, Belgium. ; The Babraham Institute, Cambridge, UK. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. rlw@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26450213" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry/*enzymology ; Class III Phosphatidylinositol 3-Kinases/chemistry/*ultrastructure ; Crystallography, X-Ray ; Endosomes/chemistry/*enzymology ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/enzymology ; Vacuolar Sorting Protein VPS15/chemistry/ultrastructure
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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    Expression, purification, crystallization and preliminary X-ray analysis of cyclophilin A from the bovine parasite Trypanosoma brucei brucei (1998)
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 54 (1998), S. 1046-1048 
    Details
    ISSN: 1399-0047
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: Cyclophilin A from the bovine parasite Trypanosoma brucei brucei has been cloned, expressed in Escherichia coli, purified and crystallized in the presence of cyclosporin A using ammonium sulfate as a precipitant. The crystals belong to the orthorhombic crystal system with unit-cell dimensions of a = 118.61, b = 210.15 and c = 153.21 Å. A data set complete to 2.7 Å has been collected using rotating-anode radiation, however the crystals diffract to at least 2.1 Å resolution using synchrotron radiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1107/S0907444998001607
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    Anomaly in α-scattering from ^6Li between 35 and 45 MeV
    Amsterdam : Elsevier
    Nuclear Physics, Section A 242 (1975), S. 149-159 
    Details
    ISSN: 0375-9474
    Keywords: Nuclear reactions
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0375-9474(75)90040-8
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