"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.


:G-protein-coupled receptors (GPCRs) represent the largest class of drug targets, accounting for more than 40% of marketed drugs; however, discovery efforts for many GPCRs have failed to provide viable drug candidates. Historically, drug discovery efforts have focused on developing ligands that act at the orthosteric site of the endogenous agonist. Recently, efforts have focused on functional assay paradigms and the discovery of ligands that act at allosteric sites to modulate receptor function in either a positive, negative, or neutral manner. Allosteric modulators have numerous advantages over orthosteric ligands, including high subtype selectivity; the ability to mimic physiological conditions; the lack of densensitization, downregulation, and internalization; and reduced side effects. Despite these virtues, challenging issues have now arisen for allosteric modulators of metabotropic glutamate receptors (mGluRs): shallow SAR, ligand-directed trafficking, and the identification of subtle "molecular switches" that modulate the modes of pharmacology. Here, we will discuss the impact of modest structural changes to multiple mGluR allosteric ligands scaffolds that unexpectedly modulate pharmacology and raise concerns over metabolism and the pharmacology of metabolites.






Wood MR,Hopkins CR,Brogan JT,Conn PJ,Lindsley CW




Has Abstract


2011-04-05 00:00:00












  • Structure and stability of apolipoprotein a-I in solution and in discoidal high-density lipoprotein probed by double charge ablation and deletion mutation.

    abstract::To identify residues and segments in the central region of apolipoprotein A-I (apoA-I) that are important for the protein structure and stability, we studied the effects of four double charge ablations, D102A/D103A, E110A/E111A, R116V/K118A, and R160V/H162A, and two deletion mutations, Delta(61-78) and Delta(121-142),...


    pub_type: 杂志文章


    authors: Gorshkova IN,Liu T,Kan HY,Chroni A,Zannis VI,Atkinson D

    更新日期:2006-01-31 00:00:00

  • Mechanistic and stereochemical studies of glycine oxidase from Bacillus subtilis strain R5.

    abstract::Glycine oxidase gene from a strain of Bacillus subtilis was cloned and expressed in Escherichia coli. The purified enzyme was found, by mass spectrometry, to have a protein M(r) of 40763 (value of 40761.6 predicted from DNA sequence) and a FAD prosthetic group M(r) of 785.1 (theoretical value of 785.5). Glycine oxidas...


    pub_type: 杂志文章


    authors: Jamil F,Gardner QA,Bashir Q,Rashid N,Akhtar M

    更新日期:2010-08-31 00:00:00

  • Specific proteolysis of human plasminogen by a 24 kDa endopeptidase from a novel Chryseobacterium Sp.

    abstract::A novel single polypeptide endopeptidase of 24 kDa (24k-endopeptidase) was purified with a yield of 300-400 microg/L from conditioned medium of a bacterial strain which was identified as a new species in the genus Chryseobacterium Sp. on the basis of its 16S rDNA sequence and DNA:DNA hybridizations. The NH(2)-terminal...


    pub_type: 杂志文章


    authors: Lijnen HR,Van Hoef B,Ugwu F,Collen D,Roelants I

    更新日期:2000-01-18 00:00:00

  • Life and Work of Stress Granules and Processing Bodies: New Insights into Their Formation and Function.

    abstract::The dynamic formation of stress granules (SGs), processing bodies (PBs), and related RNA organelles regulates diverse cellular processes, including the coordination of functionally connected messengers, the translational regulation at the synapse, and the control of viruses and retrotransposons. Recent studies have sh...


    pub_type: 杂志文章


    authors: Perez-Pepe M,Fernández-Alvarez AJ,Boccaccio GL

    更新日期:2018-05-01 00:00:00

  • Heterotropic effectors promote a global conformational change in aspartate transcarbamoylase.

    abstract::The sigmoidal dependence of activity on substrate concentration exhibited by the regulatory enzyme aspartate transcarbamoylase (ATCase) of Escherichia coli is generally attributed to a ligand-promoted change in the quaternary structure of the enzyme. Although a global conformational change in ATCase upon the binding o...


    pub_type: 杂志文章


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    更新日期:1990-04-17 00:00:00

  • Crystallographic study of Glu58Ala RNase T1 x 2'-guanosine monophosphate at 1.9-A resolution.

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  • Polymorphism of F-actin assembly. 2. Effects of barbed end capping on F-actin assembly.

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    pub_type: 杂志文章


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    更新日期:1996-04-23 00:00:00

  • Profiling Aglycon-Recognizing Sites of UDP-glucose:glycoprotein Glucosyltransferase by Means of Squarate-Mediated Labeling.

    abstract::Because of its ability to selectively glucosylate misfolded glycoproteins, UDP-glucose:glycoprotein glucosyltransferase (UGGT) functions as a folding sensor in the glycoprotein quality control system in the endoplasmic reticulum (ER). The unique property of UGGT derives from its ability to transfer a glucose residue t...


    pub_type: 杂志文章


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    pub_type: 杂志文章


    authors: Zaheer A,Lim R

    更新日期:1996-05-21 00:00:00

  • Calcium-Induced Lipid Nanocluster Structures: Sculpturing of the Plasma Membrane.

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    pub_type: 杂志文章


    authors: Hallock MJ,Greenwood AI,Wang Y,Morrissey JH,Tajkhorshid E,Rienstra CM,Pogorelov TV

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  • Library Selection with a Randomized Repertoire of (βα)8-Barrel Enzymes Results in Unexpected Induction of Gene Expression.

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    pub_type: 杂志文章


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    更新日期:1996-06-25 00:00:00

  • Structural analysis of O2'-methyl-5-carbamoylmethyluridine, a newly discovered constituent of yeast transfer RNA.

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    pub_type: 杂志文章


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    pub_type: 杂志文章


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    更新日期:2005-04-19 00:00:00

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    pub_type: 杂志文章


    authors: VanZile ML,Cosper NJ,Scott RA,Giedroc DP

    更新日期:2000-09-26 00:00:00

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    pub_type: 杂志文章


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    更新日期:1994-03-29 00:00:00

  • Mutagenesis of the uncoupling protein of brown adipose tissue. Neutralization Of E190 largely abolishes pH control of nucleotide binding.

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    pub_type: 杂志文章


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    更新日期:1997-07-08 00:00:00

  • Exposure of endogenous phosphatidylserine at the outer surface of stimulated platelets is reversed by restoration of aminophospholipid translocase activity.

    abstract::Phosphatidylserine (PS) in the plasma membrane of nonactivated human platelets is almost entirely located on the cytoplasmic side. Stimulation of platelets with the Ca2+ ionophore A23187 or combined action of collagen plus thrombin results in a rapid loss of the asymmetric distribution of PS. Also, treatment with the ...


    pub_type: 杂志文章


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    更新日期:1989-03-21 00:00:00

  • Crystal and molecular structure of a new Z-DNA crystal form: d[CGT(2-NH2-A)CG] and its platinated derivative.

    abstract::The three-dimensional structure of d[CGTA'CG], where A' = [2-NH2-A], was determined to atomic (1.35 A) resolution by single isomorphous replacement. The d[CGTA'CG] hexamer crystallizes in space group P3221, and is not isomorphous with other DNA hexanucleotides. Despite completely different crystal packing, the essenti...


    pub_type: 杂志文章


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    更新日期:1995-11-28 00:00:00

  • Notomastus lobatus chloroperoxidase and Amphitrite ornata dehaloperoxidase both contain histidine as their proximal heme iron ligand.

    abstract::Two novel heme-containing peroxidases, one able to incorporate halogens into aromatic substrates and the other able to remove them, have recently been isolated from marine sources and initially characterized by Chen et al. [(1991) J. Biol. Chem. 266, 23909-23915; (1996) J. Biol. Chem. 271, 4609-4612]. The haloperoxida...


    pub_type: 杂志文章


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    更新日期:1997-02-25 00:00:00

  • Structural analysis of the PsbQ protein of photosystem II by Fourier transform infrared and circular dichroic spectroscopy and by bioinformatic methods.

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    pub_type: 杂志文章


    authors: Balsera M,Arellano JB,Gutiérrez JR,Heredia P,Revuelta JL,De Las Rivas J

    更新日期:2003-02-04 00:00:00

  • Structural studies of two mutants of amicyanin from Paracoccus denitrificans that stabilize the reduced state of the copper.

    abstract::Mutation of Pro94 to phenylalanine or alanine significantly alters the redox properties of the type I copper center of amicyanin. Each mutation increases the redox midpoint potential (E(m)) value by at least 140 mV and shifts the pK(a) for the pH dependence of the E(m) value to a more acidic value. Atomic resolution (...


    pub_type: 杂志文章


    authors: Carrell CJ,Sun D,Jiang S,Davidson VL,Mathews FS

    更新日期:2004-07-27 00:00:00

  • Hydroperoxidase II of Escherichia coli exhibits enhanced resistance to proteolytic cleavage compared to other catalases.

    abstract::Catalase (hydroperoxidase) HPII of Escherichia coli is the largest catalase so far characterized, existing as a homotetramer of 84 kDa subunits. Each subunit has a core structure that closely resembles small subunit catalases, supplemented with an extended N-terminal sequence and compact flavodoxin-like C-terminal dom...


    pub_type: 杂志文章


    authors: Chelikani P,Donald LJ,Duckworth HW,Loewen PC

    更新日期:2003-05-20 00:00:00

  • Polypeptides of nonpolyribosomal messenger ribonucleoprotein complexes of sea urchin eggs.

    abstract::RNA competent in directing protein synthesis is sequestered in unfertilized sea urchin eggs as translationally quiescent, nonpolyribosomal, messenger ribonucleoprotein complexes (mRNPs). Following fertilization, these mRNPs are derepressed and actively translated, presumably due to changes in the mRNA-associated prote...


    pub_type: 杂志文章


    authors: Moon RT,Moe KD,Hille MB

    更新日期:1980-06-10 00:00:00

  • The role of serine 167 in human indoleamine 2,3-dioxygenase: a comparison with tryptophan 2,3-dioxygenase.

    abstract::The initial step in the l-kynurenine pathway is oxidation of l-tryptophan to N-formylkynurenine and is catalyzed by one of two heme enzymes, tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO). Here, we address the role of the conserved active site Ser167 residue in human IDO (S167A and S167H variant...


    pub_type: 杂志文章


    authors: Chauhan N,Basran J,Efimov I,Svistunenko DA,Seward HE,Moody PC,Raven EL

    更新日期:2008-04-22 00:00:00

  • Conformational change coupling the dimerization and activation of KSHV protease.

    abstract::The mechanism of herpesviral protease activation upon dimerization was studied using two independent spectroscopic assays augmented by directed mutagenesis. Spectroscopic changes, attributable to dimer interface conformational plasticity, were observed upon dimerization of Kaposi's sarcoma-associated herpesvirus prote...


    pub_type: 杂志文章


    authors: Pray TR,Reiling KK,Demirjian BG,Craik CS

    更新日期:2002-02-05 00:00:00

  • Methionine sulfoxide cytochrome c.

    abstract::Cytochrome c has been chemically modified by methylene blue mediated photooxidation. It is established that the methionine residues of the protein have been specifically converted to methionine sulfoxide residues. No oxidation of any other amino acid residues or the cysteine thioether bridges of the molecule occurs du...


    pub_type: 杂志文章


    authors: Ivanetich KM,Bradshaw JJ,Kaminsky LS

    更新日期:1976-03-09 00:00:00

  • Oxidation of cytochrome c peroxidase to compound I by peroxyacids: evidence for rate-limiting diffusion through the protein matrix.

    abstract::The rate of the reaction between p-nitroperoxybenzoic acid and cytochrome c peroxidase (CcP) has been investigated as a function of pH and ionic strength. The pH dependence of the reaction between CcP and peracetic acid has also been determined. The rate of the reactions are influenced by two heme-linked ionizations i...


    pub_type: 杂志文章


    authors: Palamakumbura AH,Foshay MC,Vitello LB,Erman JE

    更新日期:1999-11-23 00:00:00

  • Isolation of peptides from the carboxyl carrier subunit of transcarboxylase. Role of the non-biotinyl peptide in assembly.

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    pub_type: 杂志文章


    authors: Ahmad F,Jacobson B,Chuang M,Brattin W,Wood HG

    更新日期:1975-04-22 00:00:00

  • Steroid-protein interactions. Human corticosteroid-binding globulin: characterization of dimer and electrophoretic variants.

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    pub_type: 杂志文章


    authors: Mickelson KE,Harding GB,Forsthoefel M,Westphal U

    更新日期:1982-02-16 00:00:00