707 results match your criteria tm6


Effects of Two Physical Training Programs on the Cognitive Status of a Group of Older Adults in Chile.

Int J Environ Res Public Health 2021 Apr 15;18(8). Epub 2021 Apr 15.

Departamento de Educación Física, Pedagogía en Educación Física, Universidad Metropolitana de Ciencias de la Educación, Santiago 7750000, Chile.

Introduction: The effect of two physical training methods on older adults should be investigated in greater depth and its results shared with the community.

Objective: To determine the effects of two types of physical training on the functional features associated with the cognitive state and the effect on a physiological mediator of growth hormone (IGF-1) in older women.

Material And Methods: Quasi-experimental study that included 12 weeks of training in two groups divided into resistance and aerobic training. Read More

View Article and Full-Text PDF

Behavior of Chemokine Receptor 6 (CXCR6) in Complex with CXCL16 Soluble form Chemokine by Molecular Dynamic Simulations: General Protein‒Ligand Interaction Model and 3D-QSAR Studies of Synthetic Antagonists.

Life (Basel) 2021 Apr 15;11(4). Epub 2021 Apr 15.

Laboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro 76010, Mexico.

The CXCR6‒CXCL16 axis is involved in several pathological processes, and its overexpression has been detected in different types of cancer, such as prostate, breast, ovary, and lung cancer, along with schwannomas, in which it promotes invasion and metastasis. Moreover, this axis is involved in atherosclerosis, type 1 diabetes, primary immune thrombocytopenia, vitiligo, and other autoimmune diseases, in which it is responsible for the infiltration of different immune system cells. The 3D structure of CXCR6 and CXCL16 has not been experimentally resolved; therefore, homology modeling and molecular dynamics simulations could be useful for the study of this signaling axis. Read More

View Article and Full-Text PDF

A modified slow sand filtration system of epikarst spring water in karst mountainous areas, China.

J Water Health 2021 Apr;19(2):229-241

Institute of Hydrogeology and Environmental Geology, Chinese Academy of Geological Sciences, No. 268 North Zhonghua Street, Xinhua District, Shijiazhuang 050061, China E-mail: Key Laboratory of Groundwater Sciences and Engineering, Ministry of Natural Resources, No. 92 East Zhongshan Road, Zhengding County, Shijiazhuang 050899, China.

Epikarst springs are commonly used for drinking water in karst mountainous areas, but they tend to bring health risks to residents because of their vulnerability. In this work, a modified slow sand filtration system (M-SSF) was established as a case study to purify and conserve the epikarst spring water. The outcomes indicate that the purification of M-SSF relies mainly on the adsorption and ion exchange of the filter medium (mixtures of heat-treated red clay and crushed limestone, MHRCCL) during the schmutzdecke juvenility, and on the schmutzdecke-formed food chain of pollutants → bacteria → protozoa after the schmutzdecke maturity. Read More

View Article and Full-Text PDF

Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects.

J Med Chem 2021 Apr 22. Epub 2021 Apr 22.

Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, 08003 Barcelona, Spain.

The activation of cannabinoid CB receptors (CBR) by Δ-tetrahydrocannabinol (THC), the main component of , induces analgesia. CBR activation, however, also causes cognitive impairment the serotonin 5HT receptor (5HTR), a component of a CBR-5HTR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CBR transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CBR-5HTR heteromer and avert THC cognitive impairment while preserving analgesia. Read More

View Article and Full-Text PDF

Molecular Dynamics Simulations for the Determination of the Characteristic Structural Differences between Inactive and Active States of Wild Type and Mutants of the Orexin2 Receptor.

J Phys Chem B 2021 May 22;125(17):4286-4298. Epub 2021 Apr 22.

Department of Physics, School of Science and Technology, Meiji University, 1-1-1 Higashi-Mita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan.

The orexin2 receptor (OX2R), which is classified as a class A G protein-coupled receptor (GPCR), is the target of our study. We performed over 20 several-microsecond-scale molecular dynamics simulations of the wild type and mutants of OX2R to extract the characteristics of the structural changes taking place in the active state. We introduced mutations that exhibited the stable inactive state and the constitutively active state in class A GPCRs. Read More

View Article and Full-Text PDF

Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors.

Elife 2021 Apr 21;10. Epub 2021 Apr 21.

Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States.

The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G-protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. Although numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here, we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties drive differences between mGluR subtypes. Read More

View Article and Full-Text PDF

Activation Mechanism of Corticotrophin Releasing Factor Receptor Type 1 Elucidated Using Molecular Dynamics Simulations.

ACS Chem Neurosci 2021 May 16;12(9):1674-1687. Epub 2021 Apr 16.

College of Science and Mathematics, Rowan University, Glassboro, New Jersey 08028, United States.

The corticotropin-releasing factor receptor type 1 (CRF1R), a member of class B G-protein-coupled receptors (GPCRs), is a good drug target for treating depression, anxiety, and other stress-related neurodisorders. However, there is no approved drug targeting the CRF1R to date, partly due to inadequate structural information and its elusive activation mechanism. Here, by use of the crystal structures of its transmembrane domain (TMD) and the N-terminal extracellular domain (ECD) as a template, a full-length homology model of CRF1R was built and its complexes with peptide agonist urocortin 1 or small molecule antagonist CP-376395 were subjected to all-atom molecular dynamics simulations. Read More

View Article and Full-Text PDF

Cryo-EM structure of the human histamine H receptor/G complex.

Nat Commun 2021 04 7;12(1):2086. Epub 2021 Apr 7.

Laboratory of Receptor Structure and Signaling, The HIT Center for Life Sciences, Harbin Institute of Technology, Harbin, China.

Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human HR in complex with a G protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for G engagement in a model of "squash to activate and expand to deactivate". Read More

View Article and Full-Text PDF

[Activation Mechanism of Prostanoid Receptors -X-ray Crystallography of EP3 Receptor].

Authors:
Kazushi Morimoto

Yakugaku Zasshi 2021 ;141(4):473-479

Department of Cell Biology, Graduate School of Medicine, Kyoto University.

Prostanoids [prostaglandins (PGs) and thromboxanes (TXs)] are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate G protein-coupled receptors (GPCRs). The nine subtypes of prostanoid receptors (DP1, DP2, EP1, EP2, EP3, EP4, FP, IP, TP) are involved in a wide range of functions, including inflammation, immune response, reproduction, and homeostasis of the intestinal mucosa and cardiovascular system. Among the prostanoid receptors, the structure of antagonist-bound DP2, which belongs to the chemoattractant receptor family, was previously determined. Read More

View Article and Full-Text PDF
January 2021

Molecular characterizations and expression profiles of transient receptor potential channels in the brown planthopper, Nilaparvata lugens.

Pestic Biochem Physiol 2021 Mar 16;173:104780. Epub 2021 Jan 16.

College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China; State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Jiangsu, China. Electronic address:

Transient receptor potential (TRP) is a superfamily of important cation channels located on the cell membrane. It can regulate almost all sensory modality and control a series of behaviors, including hearing, locomotion, gentle touch, temperature sensation, dry air and food texture detection. The expression profiles of TRP channels have been well documented in the model insect Drosophila melanogaster. Read More

View Article and Full-Text PDF

Ligand modulation of the conformational dynamics of the A adenosine receptor revealed by single-molecule fluorescence.

Sci Rep 2021 Mar 15;11(1):5910. Epub 2021 Mar 15.

Department of Physics, University of Toronto, Toronto, ON, M5S 1A7, Canada.

G protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins, making them an important target for therapeutics. Activation of these receptors is modulated by orthosteric ligands, which stabilize one or several states within a complex conformational ensemble. The intra- and inter-state dynamics, however, is not well documented. Read More

View Article and Full-Text PDF

Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, United States.

Background And Aims: Human TM6SF2 variant rs58542926 is associated with nonalcoholic fatty liver disease (NAFLD) and hepatocellular cancer (HCC). However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased VLDL secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. Read More

View Article and Full-Text PDF
February 2021

Deciphering the Mechanism of Inhibition of SERCA1a by Sarcolipin Using Molecular Simulations.

Front Mol Biosci 2020 4;7:606254. Epub 2021 Feb 4.

CNRS UMR9187 / INSERM U1196, Institut Curie, PSL Research University, Université Paris-Saclay, Orsay, France.

SERCA1a is an ATPase calcium pump that transports Ca from the cytoplasm to the sarco/endoplasmic reticulum lumen. Sarcolipin (SLN), a transmembrane peptide, regulates the activity of SERCA1a by decreasing its Ca transport rate, but its mechanism of action is still not well-understood. To decipher this mechanism, we have performed normal mode analysis in the all-atom model, with the SERCA1a-SLN complex, or the isolated SERCA1a, embedded in an explicit membrane. Read More

View Article and Full-Text PDF
February 2021

Discovery of a true bivalent dopamine D receptor agonist.

Eur J Med Chem 2021 Feb 4;212:113151. Epub 2021 Jan 4.

Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium. Electronic address:

Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing DR. Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a DR homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays. Read More

View Article and Full-Text PDF
February 2021

Structural Assessment of Agonist Efficacy in the μ-Opioid Receptor: Morphine and Fentanyl Elicit Different Activation Patterns.

J Chem Inf Model 2021 Mar 15;61(3):1251-1274. Epub 2021 Jan 15.

Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.

Over the past two decades, the opioid epidemic in the United States and Canada has evidenced the need for a better understanding of the molecular mechanisms of medications used to fight pain. Morphine and fentanyl are widely used in opiate-mediated analgesia for the treatment of chronic pain. These compounds target the μ-opioid receptor (MOR), a class A G protein-coupled receptor (GPCR). Read More

View Article and Full-Text PDF

Probing biased activation of mu-opioid receptor by the biased agonist PZM21 using all atom molecular dynamics simulation.

Life Sci 2021 Mar 11;269:119026. Epub 2021 Jan 11.

College of Science and Mathematics, Rowan University, Glassboro, NJ 08028, USA. Electronic address:

Morphine is a commonly used opioid drug to treat acute pain by binding to the mu-opioid receptor (MOR), but its effective analgesic efficacy via triggering of the heterotrimeric G protein pathway is accompanied by a series of adverse side effects via triggering of the β-arrestin pathway. Recently, PZM21, a recently developed MOR biased agonist, shows preferentially activating the G protein pathway over β-arrestin pathway. However, there is no high-resolution receptor structure in complex with PZM21 and its action mechanism remains elusive. Read More

View Article and Full-Text PDF

Trifluorinated Keto-Enol Tautomeric Switch in Probing Domain Rotation of a G Protein-Coupled Receptor.

Bioconjug Chem 2021 01 30;32(1):99-105. Epub 2020 Dec 30.

Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida 33620, United States.

Conformational dynamics and transitions of biologically active molecules are pivotal for understanding the physiological responses they elicit. In the case of receptor activation, there are major implications elucidating disease mechanisms and drug discovery innovation. Yet, incorporation of these factors into drug screening systems remains challenging in part due to the lack of suitable approaches to include them. Read More

View Article and Full-Text PDF
January 2021

Viewing rare conformations of the β adrenergic receptor with pressure-resolved DEER spectroscopy.

Proc Natl Acad Sci U S A 2020 12 30;117(50):31824-31831. Epub 2020 Nov 30.

Jules Stein Eye Institute, University of California, Los Angeles, CA 90095;

The β adrenergic receptor (βAR) is an archetypal G protein coupled receptor (GPCR). One structural signature of GPCR activation is a large-scale movement (ca. 6 to 14 Å) of transmembrane helix 6 (TM6) to a conformation which binds and activates a cognate G protein. Read More

View Article and Full-Text PDF
December 2020

Statistics for the analysis of molecular dynamics simulations: providing P values for agonist-dependent GPCR activation.

Sci Rep 2020 11 17;10(1):19942. Epub 2020 Nov 17.

Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.

Molecular dynamics (MD) is the common computational technique for assessing efficacy of GPCR-bound ligands. Agonist efficacy measures the capability of the ligand-bound receptor of reaching the active state in comparison with the free receptor. In this respect, agonists, neutral antagonists and inverse agonists can be considered. Read More

View Article and Full-Text PDF
November 2020

The evolution and functional characterization of CXC chemokines and receptors in lamprey.

Dev Comp Immunol 2021 Mar 22;116:103905. Epub 2020 Oct 22.

Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China. Electronic address:

Chemokines are a large family of soluble peptides guiding cell migration in development and immune defense. They interact with chemokine receptors and are essential for the coordination of cell migration in diverse physiological processes. The CXC subfamily is one of the largest groups in the chemokine family and consists of multiple members. Read More

View Article and Full-Text PDF

A non-helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition.

EMBO J 2021 01 6;40(1):e105164. Epub 2020 Nov 6.

Department of Molecular Biology and Genetics, Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus C, Denmark.

MhsT of Bacillus halodurans is a transporter of hydrophobic amino acids and a homologue of the eukaryotic SLC6 family of Na -dependent symporters for amino acids, neurotransmitters, osmolytes, or creatine. The broad range of transported amino acids by MhsT prompted the investigation of the substrate recognition mechanism. Here, we report six new substrate-bound structures of MhsT, which, in conjunction with functional studies, reveal how the flexibility of a Gly-Met-Gly (GMG) motif in the unwound region of transmembrane segment 6 (TM6) is central for the recognition of substrates of different size by tailoring the binding site shape and volume. Read More

View Article and Full-Text PDF
January 2021

Structural Basis for Activation of the Heterodimeric GABA Receptor.

J Mol Biol 2020 11 12;432(22):5966-5984. Epub 2020 Oct 12.

Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea. Electronic address:

The neurotransmitter γ-aminobutyric acid (GABA) activates the metabotropic GABA receptor to generate slow, prolonged inhibitory signals that regulate the neural circuitry. The GABA receptor is an obligate heterodimeric G protein-coupled receptor (GPCR) comprised of GBR1 and GBR2 subunits, each with extracellular, seven-helix transmembrane (7TM), and coiled-coil domains. To understand how GABA-driven conformational changes in the extracellular domain are transmitted to the 7TM domain during signal transduction, we determined cryo-electron microscopy (EM) structures of GABA in two different states: an antagonist-bound inactive state, and an active state in which both the GABA agonist and a positive allosteric modulator (PAM) are bound. Read More

View Article and Full-Text PDF
November 2020

ortholog of () promoter exhibits floral-specific activity in .

PeerJ 2020 17;8:e9827. Epub 2020 Sep 17.

CAS Key Laboratory of Tropical Plant Resources and Sustainable Use, Xishuangbanna Tropical Botanical Garden, Innovation Academy for Seed Design, Chinese Academy of Sciences, Menglun, Mengla, Yunnan, China.

Background: L., a perennial oilseed plant, is considered as a promising feedstock for biodiesel production. Genetic modification of flowering characteristics is critical for breeding. Read More

View Article and Full-Text PDF
September 2020

Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.

Nat Chem Biol 2020 12 14;16(12):1368-1375. Epub 2020 Sep 14.

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Read More

View Article and Full-Text PDF
December 2020

Analysis of βAR-G and βAR-G complex formation by NMR spectroscopy.

Proc Natl Acad Sci U S A 2020 09 31;117(37):23096-23105. Epub 2020 Aug 31.

Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China;

The β-adrenergic receptor (βAR) is a prototypical G protein-coupled receptor (GPCR) that preferentially couples to the stimulatory G protein G and stimulates cAMP formation. Functional studies have shown that the βAR also couples to inhibitory G protein G, activation of which inhibits cAMP formation [R. P. Read More

View Article and Full-Text PDF
September 2020

Elucidation of Mechanism for Ligand Efficacy at Leukotriene B Receptor 2 (BLT2).

ACS Med Chem Lett 2020 Aug 14;11(8):1529-1534. Epub 2020 Jul 14.

Department of Bioinformatics, Korea University, 2511 Sejong-ro, Sejong 30019, Republic of Korea.

G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B receptor (BLT2). Read More

View Article and Full-Text PDF

Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode.

Nat Commun 2020 08 19;11(1):4160. Epub 2020 Aug 19.

Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan.

Ghrelin is a gastric peptide hormone with important physiological functions. The unique feature of ghrelin is its Serine 3 acyl-modification, which is essential for ghrelin's activity. However, it remains to be elucidated why the acyl-modification of ghrelin is necessary for activity. Read More

View Article and Full-Text PDF

An investigation into the allosteric mechanism of GPCR A adenosine receptor with trajectory-based information theory and complex network model.

J Biomol Struct Dyn 2020 Aug 3:1-9. Epub 2020 Aug 3.

Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China.

G protein-coupled receptors (GPCRs), a large superfamily of transmembrane (TM) proteins, allosterically transduce the signal of ligand binding in the extracellular (EC) domain to couple to effector proteins in the intracellular (IC) domain, therefore forming the largest class of drug targets. The A adenosine receptor (AAR), a class-A GPCR, has been extensively studied as it offers numerous possibilities for therapeutic applications. However, the mechanism of allosteric communication between EC and IC domains is not completely clear. Read More

View Article and Full-Text PDF

Structural insights into differences in G protein activation by family A and family B GPCRs.

Science 2020 07;369(6503)

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.

Family B heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-G protein complexes reveal a disruption in the α-helix of transmembrane segment 6 (TM6) not observed in family A GPCRs. To investigate the functional impact of this structural difference, we compared the structure and function of the glucagon receptor (GCGR; family B) with the β adrenergic receptor (βAR; family A). Read More

View Article and Full-Text PDF

A structural framework for unidirectional transport by a bacterial ABC exporter.

Proc Natl Acad Sci U S A 2020 08 23;117(32):19228-19236. Epub 2020 Jul 23.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;

The ATP-binding cassette (ABC) transporter of mitochondria (Atm1) mediates iron homeostasis in eukaryotes, while the prokaryotic homolog from (Atm1) can export glutathione derivatives and confer protection against heavy-metal toxicity. To establish the structural framework underlying the Atm1 transport mechanism, we determined eight structures by X-ray crystallography and single-particle cryo-electron microscopy in distinct conformational states, stabilized by individual disulfide crosslinks and nucleotides. As Atm1 progresses through the transport cycle, conformational changes in transmembrane helix 6 (TM6) alter the glutathione-binding site and the associated substrate-binding cavity. Read More

View Article and Full-Text PDF