Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor.

Abstract:

:Positive allosteric modulation of the mu-opioid receptor (MOPr), the site of action of all clinically used opioids, represents a potential approach for the management of pain. We recently reported on positive allosteric modulators of MOPr (mu-PAMs), a class A G protein coupled receptor (GPCR). This study was designed to examine the mechanism of allostery by comparing the degree to which opioid ligand structure governs modulation. To do this we examined the interaction of the mu-PAM, BMS-986122, with a chemically diverse range of MOPr orthosteric ligands. Generally, for full agonists BMS-986122 enhanced the binding affinity and potency to activate G protein with no alteration in the maximal effect. In contrast, lower efficacy agonists including morphine were insensitive to alterations in binding affinity and showed little to no change in potency to stimulate G protein. Instead, there was an increase in maximal G protein stimulation. Antagonists were unresponsive to the modulatory effects of BMS-986122. Sodium is a known endogenous allosteric modulator of MOPr and alters orthosteric agonist affinity and efficacy. The sensitivity of an orthosteric ligand to BMS-986122 was strongly correlated with its sensitivity to NaCl. In addition, BMS-986122 decreased the ability of NaCl to modulate agonist binding in an allosteric fashion. Overall, BMS-986122 displayed marked probe dependence that was based upon the efficacy of the orthosteric ligand and can be explained using the Monod-Wyman-Changeux two-state model of allostery. Furthermore, disruption of the Na(+) ion binding site may represent a common mechanism for allosteric modulation of class A GPCRs.

authors

Livingston KE,Traynor JR

doi

10.1073/pnas.1415013111

subject

Has Abstract

pub_date

2014-12-23 00:00:00

pages

18369-74

issue

51

eissn

0027-8424

issn

1091-6490

pii

1415013111

journal_volume

111

pub_type

杂志文章
  • Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma.

    abstract::Renal cell carcinoma (RCC) and normal kidney tissues have been examined from 34 patients with sporadic, nonhereditary RCC. Eighteen of the 21 cytogenetically examined tumors (86%) had a detectable anomaly of chromosome arm 3p distal to band 3p11.2-p13, manifested as a deletion, combined with the nonreciprocal transloc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.5.1571

    authors: Kovacs G,Erlandsson R,Boldog F,Ingvarsson S,Müller-Brechlin R,Klein G,Sümegi J

    更新日期:1988-03-01 00:00:00

  • Transient Darwinian selection in Salmonella enterica serovar Paratyphi A during 450 years of global spread of enteric fever.

    abstract::Multiple epidemic diseases have been designated as emerging or reemerging because the numbers of clinical cases have increased. Emerging diseases are often suspected to be driven by increased virulence or fitness, possibly associated with the gain of novel genes or mutations. However, the time period over which humans...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1411012111

    authors: Zhou Z,McCann A,Weill FX,Blin C,Nair S,Wain J,Dougan G,Achtman M

    更新日期:2014-08-19 00:00:00

  • Rate of spontaneous mutation at human loci encoding protein structure.

    abstract::The techniques of electrophoresis were used in a search for evidence of mutation affecting protein structure, the indicators being hemoglobin and a set of serum proteins and erythrocyte enzymes. Among 94,796 locus tests on Amerindians from Central and South America, there was no evidence for mutation. Among 105,649 lo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.10.6037

    authors: Neel JV,Mohrenweiser HW,Meisler MH

    更新日期:1980-10-01 00:00:00

  • Accurate estimation of influenza epidemics using Google search data via ARGO.

    abstract::Accurate real-time tracking of influenza outbreaks helps public health officials make timely and meaningful decisions that could save lives. We propose an influenza tracking model, ARGO (AutoRegression with GOogle search data), that uses publicly available online search data. In addition to having a rigorous statistic...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1515373112

    authors: Yang S,Santillana M,Kou SC

    更新日期:2015-11-24 00:00:00

  • Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy.

    abstract::Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1917891117

    authors: Chen G,Chen Z,Wen D,Wang Z,Li H,Zeng Y,Dotti G,Wirz RE,Gu Z

    更新日期:2020-02-18 00:00:00

  • On constructing folding heteropolymers.

    abstract::Simplified models of the protein-folding process have led to valuable insights into the generic properties of the folding of heteropolymers. On the basis of theoretical arguments, Shakhnovich and Gutin [(1993) Proc. Natl. Acad. Sci. USA 90, 7195-7199] have proposed a specific method to generate folding sequences for o...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.19.8798

    authors: Ebeling M,Nadler W

    更新日期:1995-09-12 00:00:00

  • Emergence of self-organized multivortex states in flocks of active rollers.

    abstract::Active matter, both synthetic and biological, demonstrates complex spatiotemporal self-organization and the emergence of collective behavior. A coherent rotational motion, the vortex phase, is of great interest because of its ability to orchestrate well-organized motion of self-propelled particles over large distances...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2000061117

    authors: Han K,Kokot G,Tovkach O,Glatz A,Aranson IS,Snezhko A

    更新日期:2020-05-05 00:00:00

  • Inducible response required for repair of low-dose radiation damage in human fibroblasts.

    abstract::Ionizing radiation (IR) induces a variety of DNA lesions among which DNA double-strand breaks (DSBs) are the biologically most significant. It is currently unclear if DSB repair is equally efficient after low and high doses. Here, we use gamma-H2AX, phospho-ATM (pATM), and 53BP1 foci analysis to monitor DSB repair. We...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1002213107

    authors: Grudzenski S,Raths A,Conrad S,Rübe CE,Löbrich M

    更新日期:2010-08-10 00:00:00

  • Activity of synthetic tat peptides in human immunodeficiency virus type 1 long terminal repeat-promoted transcription in a cell-free system.

    abstract::The tat protein encoded by the human immunodeficiency virus type 1 is a potent trans-activator of gene expression from the viral long terminal repeat. The domains that are essential for trans-activation, a Pro-Xaa3-Pro triad, a cysteine-rich metal-binding sequence motif, and a cluster of basic residues, are present wi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.18.7030

    authors: Jeyapaul J,Reddy MR,Khan SA

    更新日期:1990-09-01 00:00:00

  • Projected impacts of climate change on salmon habitat restoration.

    abstract::Throughout the world, efforts are under way to restore watersheds, but restoration planning rarely accounts for future climate change. Using a series of linked models of climate, land cover, hydrology, and salmon population dynamics, we investigated the impacts of climate change on the effectiveness of proposed habita...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0701685104

    authors: Battin J,Wiley MW,Ruckelshaus MH,Palmer RN,Korb E,Bartz KK,Imaki H

    更新日期:2007-04-17 00:00:00

  • Perturbation of the T cell repertoire in rheumatoid arthritis.

    abstract::Aberrations in the T cell repertoire with the emergence of oligoclonal populations have been described in patients with rheumatoid arthritis (RA). However, the extent of the repertoire perturbations as well as the underlying mechanisms are not known. We now have examined the diversity of the peripheral CD4 T cell repe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.24.14447

    authors: Wagner UG,Koetz K,Weyand CM,Goronzy JJ

    更新日期:1998-11-24 00:00:00

  • Induction of multiple signaling loops by MuSK during neuromuscular synapse formation.

    abstract::At the neuromuscular junction, two motor neuron-derived signals have been implicated in the regulation of synaptogenesis. Neuregulin-1 is thought to induce transcription of acetylcholine receptor (AChR) genes in subsynaptic muscle nuclei by activating ErbB receptors. Neural agrin aggregates AChRs by activating the rec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.251291598

    authors: Moore C,Leu M,Müller U,Brenner HR

    更新日期:2001-12-04 00:00:00

  • Heterogeneity of human high density lipoprotein: presence of lipoproteins with and without apoE and their roles as substrates for lecithin:cholesterol acyltransferase reaction.

    abstract::By affinity chromatography on heparin-Sepharose, two classes of lipoproteins were separated from high density lipoproteins (HDL) isolated from patients with primary or secondary lecithin:cholesterol acyltransferase (LCATase; EC 2.3.1.43) deficiency and from normal subjects. The unretained fraction, HDL(A), was charact...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.5.2969

    authors: Marcel YL,Vezina C,Emond D,Suzue G

    更新日期:1980-05-01 00:00:00

  • Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity.

    abstract::NAPVSIPQ (NAP), an active fragment of the glial-derived activity-dependent neuroprotective protein, is protective at femtomolar concentrations against a wide array of neural insults and prevents ethanol-induced fetal wastage and growth retardation in mice. NAP also antagonizes ethanol inhibition of L1-mediated cell ad...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1331636100

    authors: Wilkemeyer MF,Chen SY,Menkari CE,Brenneman DE,Sulik KK,Charness ME

    更新日期:2003-07-08 00:00:00

  • Detection of proopiomelanocortin mRNA by in situ hybridization with an oligonucleotide probe.

    abstract::Synthetic oligonucleotide probes can be easily obtained and used, in contrast to cDNA cloning to develop probes, and thus the present study was carried out to determine whether such probes could also be useful for in situ hybridization. A 24-base synthetic oligonucleotide complementary to part of the alpha-melanocyte-...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.15.5419

    authors: Lewis ME,Sherman TG,Burke S,Akil H,Davis LG,Arentzen R,Watson SJ

    更新日期:1986-08-01 00:00:00

  • MAC5, an RNA-binding protein, protects pri-miRNAs from SERRATE-dependent exoribonuclease activities.

    abstract::MAC5 is a component of the conserved MOS4-associated complex. It plays critical roles in development and immunity. Here we report that MAC5 is required for microRNA (miRNA) biogenesis. MAC5 interacts with Serrate (SE), which is a core component of the microprocessor that processes primary miRNA transcripts (pri-miRNAs...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2008283117

    authors: Li S,Li M,Liu K,Zhang H,Zhang S,Zhang C,Yu B

    更新日期:2020-09-22 00:00:00

  • The A gamma-globin 3' element provides no unique function(s) for human beta-globin locus gene regulation.

    abstract::The human beta-globin locus is activated transcriptionally by a complex series of events that culminate in appropriate temporal and tissue-specific control over five separate genes during embryonic and early postnatal development. One cis-regulatory element in the locus, originally identified as an enhancer 3' to the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.17.9944

    authors: Liu Q,Tanimoto K,Bungert J,Engel JD

    更新日期:1998-08-18 00:00:00

  • Genetic assignment of resonances in the NMR spectrum of a protein: lac repressor.

    abstract::By using a systematic genetic approach, the resonances in the 19F NMR spectrum of 3-fluorotyrosine-substituted lac repressor protein have been assigned. The NMR data indicate that each monomer of the repressor consists of two distinct and independent domains. One domain, the NH2-terminal sixth of the primary sequence,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.5.2707

    authors: Jarema MA,Lu P,Miller JH

    更新日期:1981-05-01 00:00:00

  • Nucleoporin MOS7/Nup88 is required for mitosis in gametogenesis and seed development in Arabidopsis.

    abstract::Angiosperm reproduction is characterized by alternate diploid sporophytic and haploid gametophytic generations. Gametogenesis shares similarities with that of animals except for the formation of the gametophyte, whereby haploid cells undergo several rounds of postmeiotic mitosis to form gametes and the accessory cells...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1421911112

    authors: Park GT,Frost JM,Park JS,Kim TH,Lee JS,Oh SA,Twell D,Brooks JS,Fischer RL,Choi Y

    更新日期:2014-12-23 00:00:00

  • Harvesting synergy from sustainable development goal interactions.

    abstract::As countries pursue sustainable development across sectors as diverse as health, agriculture, and infrastructure, sectoral policies interact, generating synergies that alter their effectiveness. Identifying those synergies ex ante facilitates the harmonization of policies and provides an important lever to achieve the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1817276116

    authors: Pedercini M,Arquitt S,Collste D,Herren H

    更新日期:2019-11-12 00:00:00

  • Efficient collective swimming by harnessing vortices through deep reinforcement learning.

    abstract::Fish in schooling formations navigate complex flow fields replete with mechanical energy in the vortex wakes of their companions. Their schooling behavior has been associated with evolutionary advantages including energy savings, yet the underlying physical mechanisms remain unknown. We show that fish can improve thei...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1800923115

    authors: Verma S,Novati G,Koumoutsakos P

    更新日期:2018-06-05 00:00:00

  • Identification of cell-specific and developmentally regulated nuclear factors that direct myeloid and lymphoid expression of the CD11a gene.

    abstract::Human CD11a/CD18 is a noncovalently associated heterodimeric receptor expressed exclusively on the surface of lymphocytes and myeloid cells. To begin to understand the mechanisms that direct the expression of the genes encoding this receptor, we have cloned and characterized the promoter region of the CD11a gene and l...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.11.5364

    authors: Shelley CS,Farokhzad OC,Arnaout MA

    更新日期:1993-06-01 00:00:00

  • Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease.

    abstract::Polycystic kidney disease (PKD) is the most common genetic cause of renal failure in humans. Several proteins that are encoded by genes associated with PKD have recently been identified in primary cilia in renal tubular epithelia. These findings have suggested that abnormalities in cilia formation and function may pla...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0836980100

    authors: Lin F,Hiesberger T,Cordes K,Sinclair AM,Goldstein LS,Somlo S,Igarashi P

    更新日期:2003-04-29 00:00:00

  • Tailor-made RNAi knockdown against triplet repeat disease-causing alleles.

    abstract::Nucleotide variations, including SNPs, in the coding regions of disease genes are important targets for RNAi treatment, which is a promising medical treatment for intractable diseases such as triplet repeat diseases. However, the identification of such nucleotide variations and the design of siRNAs conferring disease ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1012153107

    authors: Takahashi M,Watanabe S,Murata M,Furuya H,Kanazawa I,Wada K,Hohjoh H

    更新日期:2010-12-14 00:00:00

  • Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine.

    abstract::In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0705346104

    authors: Marutle A,Ohmitsu M,Nilbratt M,Greig NH,Nordberg A,Sugaya K

    更新日期:2007-07-24 00:00:00

  • Drosophila IRBP bZIP heterodimer binds P-element DNA and affects hybrid dysgenesis.

    abstract::In Drosophila, P-element transposition causes mutagenesis and genome instability during hybrid dysgenesis. The P-element 31-bp terminal inverted repeats (TIRs) contain sequences essential for transposase cleavage and have been implicated in DNA repair via protein-DNA interactions with cellular proteins. The identity a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1613508113

    authors: Francis MJ,Roche S,Cho MJ,Beall E,Min B,Panganiban RP,Rio DC

    更新日期:2016-11-15 00:00:00

  • Isolation and characterization of a temperature-sensitive mutant of avian myeloblastosis virus.

    abstract::A temperature-sensitive (ts) mutant, GA 907/7, was isolated after mutagen treatment of avian myeloblastosis virus. When bone marrow cells or secondary yolk sac macrophages were infected with GA 907/7, the expression of transformation was greatly reduced at 41 degrees C. The results of temperature-shift experiments sug...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.5.1421

    authors: Moscovici MG,Moscovici C

    更新日期:1983-03-01 00:00:00

  • Neural reactivation in parietal cortex enhances memory for episodically linked information.

    abstract::Remembering is a complex process that involves recalling specific details, such as who you were with when you celebrated your last birthday, as well as contextual information, such as the place where you celebrated. It is well established that the act of remembering enhances long-term retention of the retrieved inform...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1800006115

    authors: Jonker TR,Dimsdale-Zucker H,Ritchey M,Clarke A,Ranganath C

    更新日期:2018-10-23 00:00:00

  • Transcriptional network underlying Caenorhabditis elegans vulval development.

    abstract::The vulval development of Caenorhabditis elegans provides an opportunity to investigate genetic networks that control gene expression during organogenesis. During the fourth larval stage (L4), seven vulval cell types are produced, each of which executes a distinct gene expression program. We analyze how the expression...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0408122102

    authors: Inoue T,Wang M,Ririe TO,Fernandes JS,Sternberg PW

    更新日期:2005-04-05 00:00:00

  • In vivo studies of fullerene-based materials using endohedral metallofullerene radiotracers.

    abstract::Biodistribution studies of a water-soluble radioactive metallofullerene compound have been conducted using BALB/c mice. To this end, a sample containing Hox@C82 (x = 1, 2) was purified and derivatized to prepare the water-soluble metallofullerol, Hox@C82(OH)y. This metallofullerol was then neutron-activated (165Ho[n,g...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.9.5182

    authors: Cagle DW,Kennel SJ,Mirzadeh S,Alford JM,Wilson LJ

    更新日期:1999-04-27 00:00:00