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  • 1
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    Structure of a beta1-adrenergic G-protein-coupled receptor (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-07-03
    Description: G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 A resolution crystal structure of a beta(1)-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane alpha-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the beta(1)-adrenergic receptor and binding of carazolol to the beta(2)-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the beta(2)-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923055/" 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/PMC2923055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warne, Tony -- Serrano-Vega, Maria J -- Baker, Jillian G -- Moukhametzianov, Rouslan -- Edwards, Patricia C -- Henderson, Richard -- Leslie, Andrew G W -- Tate, Christopher G -- Schertler, Gebhard F X -- MC_U105178937/Medical Research Council/United Kingdom -- MC_U105184322/Medical Research Council/United Kingdom -- MC_U105184325/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- U.1051.04.020(78937)/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Jul 24;454(7203):486-91. doi: 10.1038/nature07101. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594507" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-1 Receptor Agonists ; Adrenergic beta-1 Receptor Antagonists ; Adrenergic beta-Antagonists/chemistry/metabolism ; Amino Acid Motifs ; Animals ; Binding Sites ; Crystallization ; Crystallography, X-Ray ; Ligands ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation ; Pindolol/analogs & derivatives/chemistry/metabolism ; Propanolamines/chemistry/metabolism ; Protein Conformation ; Receptors, Adrenergic, beta-1/*chemistry/metabolism ; Thermodynamics ; Turkeys
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    The structural basis for agonist and partial agonist action on a beta(1)-adrenergic receptor (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-01-14
    Description: beta-adrenergic receptors (betaARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit betaARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) beta(1)-adrenergic receptor (beta(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 A contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023143/" 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/PMC3023143/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warne, Tony -- Moukhametzianov, Rouslan -- Baker, Jillian G -- Nehme, Rony -- Edwards, Patricia C -- Leslie, Andrew G W -- Schertler, Gebhard F X -- Tate, Christopher G -- BB/G003653/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184325/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- U.1051.04.034/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Jan 13;469(7329):241-4. doi: 10.1038/nature09746.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21228877" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-1 Receptor Agonists/*chemistry/metabolism/*pharmacology ; Adrenergic beta-1 Receptor Antagonists/*chemistry/metabolism/*pharmacology ; Albuterol/chemistry/metabolism/pharmacology ; Amphetamines/chemistry/metabolism/pharmacology ; Animals ; Binding Sites ; Catecholamines/metabolism ; Crystallography, X-Ray ; Dobutamine/chemistry/metabolism/pharmacology ; Drug Design ; *Drug Partial Agonism ; Hydrogen Bonding ; Hydroxyquinolines/chemistry/metabolism/pharmacology ; Isoproterenol/chemistry/metabolism/pharmacology ; Ligands ; Models, Molecular ; Protein Conformation ; Protein Stability/drug effects ; Receptors, Adrenergic, beta-1/*chemistry/*metabolism ; Serine/chemistry/metabolism ; Structure-Activity Relationship ; Turkeys
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-05-20
    Description: Adenosine receptors and beta-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism. Recent structures of beta-adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors. Here we present two crystal structures of the thermostabilized human adenosine A(2A) receptor (A(2A)R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. 8). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand-binding pocket where it makes polar interactions with conserved residues in H7 (Ser 277(7.42) and His 278(7.43); superscripts refer to Ballesteros-Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A(2A)R with the agonist-bound structures of beta-adrenoceptors indicates that the contraction of the ligand-binding pocket caused by the inward motion of helices 3, 5 and 7 may be a common feature in the activation of all GPCRs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146096/" 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/PMC3146096/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lebon, Guillaume -- Warne, Tony -- Edwards, Patricia C -- Bennett, Kirstie -- Langmead, Christopher J -- Leslie, Andrew G W -- Tate, Christopher G -- BB/G003653/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184325/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- U.1051.04.034/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2011 May 18;474(7352):521-5. doi: 10.1038/nature10136.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21593763" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/chemistry/metabolism/pharmacology ; Adenosine A2 Receptor Agonists/*metabolism/pharmacology ; Adenosine-5'-(N-ethylcarboxamide)/chemistry/metabolism/pharmacology ; Animals ; Binding Sites ; CHO Cells ; Cricetinae ; Cricetulus ; Crystallography, X-Ray ; Drug Inverse Agonism ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Receptor, Adenosine A2A/*chemistry/*metabolism ; Triazines/metabolism/pharmacology ; Triazoles/metabolism/pharmacology
    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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    Two distinct conformations of helix 6 observed in antagonist-bound structures of a  1-adrenergic receptor (2011)
    National Academy of Sciences
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    Publication Date: 2011-05-03
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Two distinct conformations of helix 6 observed in antagonist-bound structures of a {beta}1-adrenergic receptor [Biochemistry] (2011)
    National Academy of Sciences
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    Publication Date: 2011-05-18
    Description: The β1-adrenergic receptor (β1AR) is a G-protein-coupled receptor whose inactive state structure was determined using a thermostabilized mutant (β1AR–M23). However, it was not thought to be in a fully inactivated state because there was no salt bridge between Arg139 and Glu285 linking the cytoplasmic ends of transmembrane helices 3 and 6 (the R3.50 - D/E6.30 “ionic lock”). Here we compare eight new structures of β1AR–M23, determined from crystallographically independent molecules in four different crystals with three different antagonists bound. These structures are all in the inactive R state and show clear electron density for cytoplasmic loop 3 linking transmembrane helices 5 and 6 that had not been seen previously. Despite significantly different crystal packing interactions, there are only two distinct conformations of the cytoplasmic end of helix 6, bent and straight. In the bent conformation, the Arg139-Glu285 salt bridge is present, as in the crystal structure of dark-state rhodopsin. The straight conformation, observed in previously solved structures of β-receptors, results in the ends of helices 3 and 6 being too far apart for the ionic lock to form. In the bent conformation, the R3.50 - E6.30 distance is significantly longer than in rhodopsin, suggesting that the interaction is also weaker, which could explain the high basal activity in β1AR compared to rhodopsin. Many mutations that increase the constitutive activity of G-protein-coupled receptors are found in the bent region at the cytoplasmic end of helix 6, supporting the idea that this region plays an important role in receptor activation.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Molecular basis for high-affinity agonist binding in GPCRs (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉G protein–coupled receptors (GPCRs) in the G protein–coupled active state have higher affinity for agonists as compared with when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β〈sub〉1〈/sub〉-adrenoceptor (β〈sub〉1〈/sub〉AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β〈sub〉1〈/sub〉AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.〈/p〉
    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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  • 7
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    Molecular basis for high-affinity agonist binding in GPCRs (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists compared to when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β〈sub〉1〈/sub〉-adrenoceptor (β〈sub〉1〈/sub〉AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β〈sub〉1〈/sub〉AR bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    Sodium/potassium selectivity and pleiotropy in stl2 , a highly salt‐tolerant mutation of Ceratopteris richardii (1999)
    Wiley
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    Publication Date: 1999-08-15
    Print ISSN: 0140-7791
    Electronic ISSN: 1365-3040
    Topics: Biology
    Published by Wiley
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  • 9
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    High salinity tolerance in the stl2 mutation of Ceratopteris richardii is associated with enhanced K+ influx and loss (1996)
    Wiley
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    Publication Date: 1996-01-01
    Print ISSN: 0140-7791
    Electronic ISSN: 1365-3040
    Topics: Biology
    Published by Wiley
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  • 10
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    Differential effects of Na+, Mg2+, K+, Ca2+ and osmotic stress on the wild type and the NaCl-tolerant mutants stl1 and stl2 of Ceratopteris richardii (1996)
    Wiley
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    Publication Date: 1996-01-01
    Print ISSN: 0140-7791
    Electronic ISSN: 1365-3040
    Topics: Biology
    Published by Wiley
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