Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors.

Abstract:

:G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.

journal_name

Int J Mol Sci

authors

Denzinger K,Nguyen TN,Noonan T,Wolber G,Bermudez M

doi

10.3390/ijms21249728

subject

Has Abstract

pub_date

2020-12-20 00:00:00

issue

24

issn

1422-0067

pii

ijms21249728

journal_volume

21

pub_type

杂志文章
  • Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease.

    abstract::Several studies indicate that bisphenol A (BPA) and phthalates may have a role in the development of metabolic diseases using different molecular pathways, including epigenetic regulatory mechanisms. However, it is unclear whether exposure to these chemicals modifies serum levels of miRNAs associated with gestational ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20133343

    authors: Martínez-Ibarra A,Martínez-Razo LD,Vázquez-Martínez ER,Martínez-Cruz N,Flores-Ramírez R,García-Gómez E,López-López M,Ortega-González C,Camacho-Arroyo I,Cerbón M

    更新日期:2019-07-07 00:00:00

  • The effect of a silver nanoparticle polysaccharide system on streptococcal and saliva-derived biofilms.

    abstract::In this work, we studied the antimicrobial properties of a nanocomposite system based on a lactose-substituted chitosan and silver nanoparticles: Chitlac-nAg. Twofold serial dilutions of the colloidal Chitlac-nAg solution were both tested on Streptococcus mitis, Streptococcus mutans, and Streptococcus oralis planktoni...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms140713615

    authors: Di Giulio M,Di Bartolomeo S,Di Campli E,Sancilio S,Marsich E,Travan A,Cataldi A,Cellini L

    更新日期:2013-06-28 00:00:00

  • Transcriptional Regulation of Acyl-CoA:Glycerol-sn-3-Phosphate Acyltransferases.

    abstract::Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms20040964

    authors: Karasawa K,Tanigawa K,Harada A,Yamashita A

    更新日期:2019-02-22 00:00:00

  • Specialist and Generalist Fungal Parasites Induce Distinct Biochemical Changes in the Mandible Muscles of Their Host.

    abstract::Some parasites have evolved the ability to adaptively manipulate host behavior. One notable example is the fungus Ophiocordyceps unilateralis sensu lato, which has evolved the ability to alter the behavior of ants in ways that enable fungal transmission and lifecycle completion. Because host mandibles are affected by ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20184589

    authors: Zheng S,Loreto R,Smith P,Patterson A,Hughes D,Wang L

    更新日期:2019-09-17 00:00:00

  • A Pilot Study for the Feasibility of Exome-Sequencing in Circulating Tumor Cells Versus Single Metastatic Biopsies in Breast Cancer.

    abstract::The comparison of the landscape of somatic alterations in circulating tumor cells (CTCs) versus metastases is challenging. Here, we comprehensively characterized the somatic landscape in bulk (amplified and non-amplified), spike-in breast cancer cells, CTCs, and metastases from breast cancer patients using whole-exome...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21144826

    authors: Kaur P,Campo D,Porras TB,Ring A,Lu J,Chairez Y,Su Y,Kang I,Lang JE

    更新日期:2020-07-08 00:00:00

  • HtrA1 Is Specifically Up-Regulated in Active Keloid Lesions and Stimulates Keloid Development.

    abstract::Keloids occur after failure of the wound healing process; inflammation persists, and various treatments are ineffective. Keloid pathogenesis is still unclear. We have previously analysed the gene expression profiles in keloid tissue and found that HtrA1 was markedly up-regulated in the keloid lesions. HtrA1 is a serin...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms19051275

    authors: Yamawaki S,Naitoh M,Kubota H,Aya R,Katayama Y,Ishiko T,Tamura T,Yoshikawa K,Enoshiri T,Ikeda M,Suzuki S

    更新日期:2018-04-24 00:00:00

  • The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester.

    abstract::Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21030806

    authors: Ellery SJ,Murthi P,Gatta PAD,May AK,Davies-Tuck ML,Kowalski GM,Callahan DL,Bruce CR,Wallace EM,Walker DW,Dickinson H,Snow RJ

    更新日期:2020-01-26 00:00:00

  • Understanding Melanocyte Stem Cells for Disease Modeling and Regenerative Medicine Applications.

    abstract::Melanocytes in the skin play an indispensable role in the pigmentation of skin and its appendages. It is well known that the embryonic origin of melanocytes is neural crest cells. In adult skin, functional melanocytes are continuously repopulated by the differentiation of melanocyte stem cells (McSCs) residing in the ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms161226207

    authors: Mull AN,Zolekar A,Wang YC

    更新日期:2015-12-21 00:00:00

  • Therapeutic Potential of Antimicrobial Peptides in Polymicrobial Biofilm-Associated Infections.

    abstract::It is widely recognized that many chronic infections of the human body have a polymicrobial etiology. These include diabetic foot ulcer infections, lung infections in cystic fibrosis patients, periodontitis, otitis, urinary tract infections and even a proportion of systemic infections. The treatment of mixed infection...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms22020482

    authors: Batoni G,Maisetta G,Esin S

    更新日期:2021-01-06 00:00:00

  • Voluntary Activity Modulates Sugar-Induced Elastic Fiber Remodeling in the Alveolar Region of the Mouse Lung.

    abstract::Diabetes and respiratory diseases are frequently comorbid conditions. However, the mechanistic links between hyperglycemia and lung dysfunction are not entirely understood. This study examined the effects of high sucrose intake on lung mechanics and alveolar septal composition and tested voluntary activity as an inter...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20102438

    authors: Hollenbach J,Lopez-Rodriguez E,Mühlfeld C,Schipke J

    更新日期:2019-05-17 00:00:00

  • Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization.

    abstract::We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-a...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21072614

    authors: Vyhlídalová B,Krasulová K,Pečinková P,Marcalíková A,Vrzal R,Zemánková L,Vančo J,Trávníček Z,Vondráček J,Karasová M,Mani S,Dvořák Z

    更新日期:2020-04-09 00:00:00

  • Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials.

    abstract::The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infe...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21155224

    authors: Al-Horani RA,Kar S,Aliter KF

    更新日期:2020-07-23 00:00:00

  • Genome-Wide Investigation of the Auxin Response Factor Gene Family in Tartary Buckwheat (Fagopyrum tataricum).

    abstract::Auxin signaling plays an important role in plant growth and development. It responds to various developmental and environmental events, such as embryogenesis, organogenesis, shoot elongation, tropical growth, lateral root formation, flower and fruit development, tissue and organ architecture, and vascular differentiat...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms19113526

    authors: Liu M,Ma Z,Wang A,Zheng T,Huang L,Sun W,Zhang Y,Jin W,Zhan J,Cai Y,Tang Y,Wu Q,Tang Z,Bu T,Li C,Chen H

    更新日期:2018-11-09 00:00:00

  • Seed Germination in Oil Palm (Elaeis guineensis Jacq.): A Review of Metabolic Pathways and Control Mechanisms.

    abstract::Oil palm is an oil-producing crop of major importance at the global scale. Oil palm mesocarp lipids are used for myriads industrial applications, and market demand has been growing for decades. In addition, oil palm seeds are oleaginous, and the oil extracted therefrom can be used for several purposes, from food to co...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21124227

    authors: Cui J,Lamade E,Tcherkez G

    更新日期:2020-06-13 00:00:00

  • Roles of Sestrin2 and Ribosomal Protein S6 in Transient Global Ischemia-Induced Hippocampal Neuronal Injury.

    abstract::Recent studies suggested that sestrin2 is a crucial modulator for the production of reactive oxygen species (ROS). In addition, sestrin2 may also regulate ribosomal protein S6 (RpS6), a molecule important for protein synthesis, through the effect of mammalian target of rapamycin (mTOR) complex that is pivotal for long...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms161125963

    authors: Chuang YC,Yang JL,Yang DI,Lin TK,Liou CW,Chen SD

    更新日期:2015-11-04 00:00:00

  • Safety Profile of TiO₂-Based Photocatalytic Nanofabrics for Indoor Formaldehyde Degradation.

    abstract::Anatase TiO₂ nanoparticles (TNPs) are synthesized using the sol-gel method and loaded onto the surface of polyester-cotton (65/35) fabrics. The nanofabrics degrade formaldehyde at an efficiency of 77% in eight hours with visible light irradiation or 97% with UV light. The loaded TNPs display very little release from n...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms161126055

    authors: Cui G,Xin Y,Jiang X,Dong M,Li J,Wang P,Zhai S,Dong Y,Jia J,Yan B

    更新日期:2015-11-19 00:00:00

  • Radiation-Induced Reactions in The Liver - Modulation of Radiation Effects by Lifestyle-Related Factors.

    abstract::Radiation has a wide variety of effects on the liver. Fibrosis is a concern in medical fields as one of the acute effects of high-dose irradiation, such as with cancer radiotherapies. Cancer is also an important concern following exposure to radiation. The liver has an active metabolism and reacts to radiations. In ad...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms19123855

    authors: Nakajima T,Ninomiya Y,Nenoi M

    更新日期:2018-12-03 00:00:00

  • Do Atypical Antipsychotics Have Antisuicidal Effects? A Hypothesis-Generating Overview.

    abstract::Modern antipsychotic drugs are employed increasingly in the treatment of mood disorders as well as psychoses, stimulating interest in their possible contributions to altering suicidal risk. Clozapine remains the only treatment with an FDA-recognized indication for reducing suicidal risk (in schizophrenia). We carried ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms17101700

    authors: Pompili M,Baldessarini RJ,Forte A,Erbuto D,Serafini G,Fiorillo A,Amore M,Girardi P

    更新日期:2016-10-11 00:00:00

  • Combined 3D-QSAR modeling and molecular docking studies on pyrrole-indolin-2-ones as Aurora A kinase inhibitors.

    abstract::Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms12031605

    authors: Ai Y,Wang ST,Sun PH,Song FJ

    更新日期:2011-01-01 00:00:00

  • Computer-Aided Estimation of Biological Activity Profiles of Drug-Like Compounds Taking into Account Their Metabolism in Human Body.

    abstract::Most pharmaceutical substances interact with several or even many molecular targets in the organism, determining the complex profiles of their biological activity. Moreover, due to biotransformation in the human body, they form one or several metabolites with different biological activity profiles. Therefore, the deve...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21207492

    authors: Filimonov DA,Rudik AV,Dmitriev AV,Poroikov VV

    更新日期:2020-10-11 00:00:00

  • Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma.

    abstract::Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dep...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms19123798

    authors: Fianco G,Contadini C,Ferri A,Cirotti C,Stagni V,Barilà D

    更新日期:2018-11-29 00:00:00

  • TPX2 is a prognostic marker and contributes to growth and metastasis of human hepatocellular carcinoma.

    abstract::Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that the expression ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms151018148

    authors: Huang Y,Guo W,Kan H

    更新日期:2014-10-09 00:00:00

  • Does Herd Immunity Exist in Aquatic Animals?

    abstract::Viral hemorrhagic septicemia virus genotype IVb (VHSV-IVb) is presently found throughout the Laurentian Great Lakes region of North America. We recently developed a DNA vaccine preparation containing the VHSV-IVb glycoprotein (G) gene with a cytomegalovirus (CMV) promoter that proved highly efficacious in protecting m...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms17111898

    authors: Standish IF,Brenden TO,Faisal M

    更新日期:2016-11-15 00:00:00

  • Novel Nanocomposite Inhibiting Caries at the Enamel Restoration Margins in an In Vitro Saliva-Derived Biofilm Secondary Caries Model.

    abstract::Secondary caries often occurs at the tooth-composite margins. This study developed a novel bioactive composite containing DMAHDM (dimethylaminohexadecyl methacrylate) and NACP (nanoparticles of amorphous calcium phosphate), inhibiting caries at the enamel restoration margins in an in vitro saliva-derived biofilm secon...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms21176369

    authors: Zhou W,Peng X,Zhou X,Bonavente A,Weir MD,Melo MAS,Imazato S,Oates TW,Cheng L,Xu HHK

    更新日期:2020-09-02 00:00:00

  • Mutagenic Study of Benzimidazole Derivatives with (+S9) and without (-S9) Metabolic Activation.

    abstract::Benzimidazole derivatives have a diverse range of biological activities, including antiulcer, antihypertensive, antiviral, antifungal, anti-inflammatory, and anticancer. Despite these activities, previous studies have revealed that some of the derivatives can induce mutations. This study aimed to screen for potential ...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms20184324

    authors: Azahar NH,Ab Dullah SS,Abdullah R,Ahmat N,Md Akim A,Ab Hamid H

    更新日期:2019-09-04 00:00:00

  • Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury.

    abstract::Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophage...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms161226145

    authors: Tsurumaki H,Mogi C,Aoki-Saito H,Tobo M,Kamide Y,Yatomi M,Sato K,Dobashi K,Ishizuka T,Hisada T,Yamada M,Okajima F

    更新日期:2015-12-04 00:00:00

  • Metabolic difference of CZ48 in human and mouse liver microsomes.

    abstract::CZ48, chemically camptothecin-20-O-propionate hydrate, is currently under clinical investigation. The kinetics of the metabolite camptothecin (CPT) formation and of CZ48 depletion in mouse and human liver microsomes in the presence or absence of NADPH was examined. The formation rate of camptothecin in human liver mic...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms13055498

    authors: Liu X,Dejesus A,Cao Z,Vardeman D,Giovanella B

    更新日期:2012-01-01 00:00:00

  • The Effect of Alendronate Loaded Biphasic Calcium Phosphate Scaffolds on Bone Regeneration in a Rat Tibial Defect Model.

    abstract::This study investigated the effect of alendronate (Aln) released from biphasic calcium phosphate (BCP) scaffolds. We evaluated the in vitro osteogenic differentiation of Aln/BCP scaffolds using MG-63 cells and the in vivo bone regenerative capability of Aln/BCP scaffolds using a rat tibial defect model with radiograph...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章

    doi:10.3390/ijms161125982

    authors: Park KW,Yun YP,Kim SE,Song HR

    更新日期:2015-11-06 00:00:00

  • Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models.

    abstract::Arthritis, including osteoarthritis (OA) and rheumatoid arthritis (RA), is the leading cause of years lived with disability (YLD) worldwide. Although pain is the cardinal symptom of arthritis, which is directly related to function and quality of life, the elucidation of the mechanism underlying the pathogenesis of pai...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21020533

    authors: Hong JI,Park IY,Kim HA

    更新日期:2020-01-14 00:00:00

  • Virus-Mediated Cell-Cell Fusion.

    abstract::Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cel...

    journal_title:International journal of molecular sciences

    pub_type: 杂志文章,评审

    doi:10.3390/ijms21249644

    authors: Leroy H,Han M,Woottum M,Bracq L,Bouchet J,Xie M,Benichou S

    更新日期:2020-12-17 00:00:00