Abstract:
:G-protein-coupled receptors (GPCRs) are important membrane proteins that mediate cellular signaling and represent primary targets for about one-third of currently marketed drugs. Recent x-ray crystallographic studies identified distinct conformations of GPCRs in the active and inactive states. An allosteric sodium ion was found bound to a highly conserved D2.50 residue in inactive GPCRs, whereas the D2.50 allosteric pocket became collapsed in active GPCR structures. However, the dynamic mechanisms underlying these observations remain elusive. In this study, we aimed to understand the mechanistic effects of sodium ion binding on dynamic activation of the M3 muscarinic GPCR through long-timescale accelerated molecular dynamics (aMD) simulations. Results showed that with the D2.50 residue deprotonated, the M3 receptor is bound by an allosteric sodium ion and confined mostly in the inactive state with remarkably reduced flexibility. In contrast, the D2.50-protonated receptor does not exhibit sodium ion binding to the D2.50 allosteric site and samples a significantly larger conformational space. The receptor activation is captured and characterized by large-scale structural rearrangements of the transmembrane helices via dynamic hydrogen bond and salt bridge interactions. The residue motions are highly correlated during receptor activation. Further network analysis revealed that the allosteric signaling between residue D2.50 and key residues in the intracellular, extracellular, and orthosteric pockets is significantly weakened upon sodium ion binding.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Miao Y,Caliman AD,McCammon JAdoi
10.1016/j.bpj.2015.03.003subject
Has Abstractpub_date
2015-04-07 00:00:00pages
1796-1806issue
7eissn
0006-3495issn
1542-0086pii
S0006-3495(15)00232-5journal_volume
108pub_type
杂志文章abstract::4',6-diamidino-2-phenylindole (DAPI), netropsin, and pentamidine are minor groove binders that have terminal -C(NH2)2+ groups. The hydration changes that accompany their binding to the minor groove of the (AATT)2 sequence have been studied using the osmotic stress technique with fluorescence spectroscopy. The affinity...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.106.097451
更新日期:2007-02-01 00:00:00
abstract::We report a simple method to obtain stable asymmetric giant unilamellar vesicles (GUVs). Fluorescence correlation spectroscopy was used to quantitatively characterize vesicle properties. After brain sphingomyelin (bSM) was exchanged into dioleoylphosphatidylcholine (DOPC) GUVs, lateral diffusion in the bSM-containing ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2010.11.051
更新日期:2011-01-05 00:00:00
abstract::Photoreverse reactions of octopus rhodopsin (Rh) from acid-metarhodopsin (Acid-Meta), which is the final product of the photoreaction of Rh, to Rh were studied by the time-resolved transient absorption and transient grating methods. The time course of the absorption signal showed a rapid change within 500 ns followed ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.106.101741
更新日期:2007-05-15 00:00:00
abstract::Spectroscopic responses of the potentiometric probe 2-(4-(dimethylamino)styryl)-1-methylpyridinium iodide (DASPMI) were investigated in living cells by means of a time- and space-correlated single photon counting technique. Spatially resolved fluorescence decays from single mitochondria or only a very few organelles o...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.108.135079
更新日期:2008-10-01 00:00:00
abstract::Current methods for screening cell receptor internalization often require complex image analysis with limited sensitivity. Here we describe a novel bioassay based on detection of changes in global fluorescence lifetime above a gold substrate, with superresolution axial sensitivity and no need for image analysis. We sh...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2010.03.016
更新日期:2010-06-02 00:00:00
abstract::Forces applied by intact mucus-propelling cilia were measured for the first time that we know of using a combined atomic force microscopy (AFM) and electrooptic system. The AFM probe was dipped into a field of beating cilia and its time-dependent deflection was recorded as it was struck by the cilia while the electroo...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.106.094698
更新日期:2007-03-01 00:00:00
abstract::Cord factor (trehalose 6,6'-dimycolate, CF) is a glycolipid located in the outer mycobacterial cell wall that is implicated in the pathogenesis of mycobacteria. Furthermore, CF is a convenient model for studying mycolic acid residues, the major lipid constituents of the mycobacterial cell wall that are believed to for...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(96)79523-1
更新日期:1996-12-01 00:00:00
abstract::Understanding cellular membrane processes is critical for the study of events such as viral entry, neurotransmitter exocytosis, and immune activation. Supported lipid bilayers are commonly used to model these membrane processes experimentally. Despite the relative simplicity of such a system, many important structural...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.103.029652
更新日期:2004-06-01 00:00:00
abstract::Purple photosynthetic bacteria harvest light using pigment-protein complexes which are often arranged in pseudo-organelles called chromatophores. A model of a chromatophore from Rhodospirillum photometricum was constructed based on atomic force microscopy data. Molecular-dynamics simulations and quantum-dynamics calcu...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2014.04.030
更新日期:2014-06-03 00:00:00
abstract::Intrinsically disordered proteins play important roles throughout biology, yet our understanding of the relationship between their sequences, structural properties, and functions remains incomplete. The dynamic nature of these proteins, however, makes them difficult to characterize structurally. Many disordered protei...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2017.06.042
更新日期:2017-08-08 00:00:00
abstract::The interaction of cells in a tissue depends on the nature of the extracellular matrix. The electrical properties of the narrow extracellular space are unknown. Here we consider cell adhesion mediated by extracellular matrix protein on a solid substrate as a model system. We culture human embryonic kidney (HEK293) cel...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.105.072587
更新日期:2006-04-01 00:00:00
abstract::We developed a multicellular model characterized by a high degree of heterogeneity to investigate possible mechanisms that underlie circadian network synchronization and rhythmicity in the suprachiasmatic nucleus (SCN). We populated a two-dimensional grid with 400 model neurons coupled via γ-aminobutyric acid (GABA) a...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2011.04.051
更新日期:2011-07-06 00:00:00
abstract::The formulation of Lorente de Nó for the potential distribution in a volume conductor due to a contained bioelectric source is reviewed. The aforementioned formula is based on data taken from the bioelectric source in air (excised). This work is extended to the derivation of a formula which depends upon quantities ava...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/s0006-3495(64)86785-0
更新日期:1964-07-01 00:00:00
abstract::Specific amino acid sequence segments have been assigned to locations in the structural map of bacteriorhodopsin using two-dimensional neutron diffraction data and a model building analysis. Models are constructed computationally by building specific regions of the amino acid sequence as alpha helices and then positio...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(83)84391-4
更新日期:1983-06-01 00:00:00
abstract::Sedimentation velocity is a powerful tool for the analysis of complex solutions of macromolecules. However, sample turbidity imposes an upper limit to the size of molecular complexes currently amenable to such analysis. Furthermore, the breadth of the particle size distribution, combined with possible variations in th...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(99)77273-5
更新日期:1999-02-01 00:00:00
abstract::Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. To gain insight into this dynamic and complex process, we studied the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) i...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2014.02.030
更新日期:2014-04-15 00:00:00
abstract::We present a theory for proton diffusion through an immobilized protein membrane perfused with an electrolyte and a buffer. Using a Nernst-Planck equation for each species and assuming local charge neutrality, we obtain two coupled nonlinear diffusion equations with new diffusion coefficients dependent on the concentr...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(79)85274-1
更新日期:1979-01-01 00:00:00
abstract::Small-angle neutron and x-ray scattering experiments have been performed on type 2 tissular transglutaminase to characterize the conformational changes that bring about Ca(2+) activation and guanosine triphosphate (GTP) inhibition. The native and a proteolyzed form of the enzyme, in the presence and in the absence of ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(00)76860-3
更新日期:2000-06-01 00:00:00
abstract::The nuclei of epididymal sperm, isolated from C57BL/6J and CBA/J inbred mice by their resistance to trypsin digestion, retain the shape differences of the intact sperm head. Various physical characteristics of these nuclei were measured and compared. The measurement of the projected dimensions of nuclei showed that th...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(76)85730-X
更新日期:1976-07-01 00:00:00
abstract::Receptor activity modifying proteins (RAMPs) are a family of single-pass transmembrane proteins that dimerize with G-protein-coupled receptors. They may alter the ligand recognition properties of the receptors (particularly for the calcitonin receptor-like receptor, CLR). Very little structural information is availabl...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.106.084582
更新日期:2006-07-15 00:00:00
abstract::Biochemical systems lose their homogeneity at a mesoscopic scale; physical parameters vary sharply over a scale of a few nanometers.In this manuscript, we demonstrate how proton diffusion studies can report the microscopic properties of inhomogeneous systems.The method used for this purpose was the laser induced proto...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(92)81584-9
更新日期:1992-07-01 00:00:00
abstract::The initial output of a time-resolved macromolecular crystallography experiment is a time-dependent series of difference electron density maps that displays the time-dependent changes in underlying structure as a reaction progresses. The goal is to interpret such data in terms of a small number of crystallographically...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2010.10.053
更新日期:2011-01-19 00:00:00
abstract::Neutrophils rely on rapid changes in morphology to ward off invaders. Time-resolved dynamics of spreading human neutrophils after activation by the chemoattractant fMLF (formyl methionyl leucyl phenylalanine) was observed by RICM (reflection interference contrast microscopy). An image-processing algorithm was develope...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1529/biophysj.105.080382
更新日期:2006-12-15 00:00:00
abstract::The functions and elasticities of the cell are largely related to the structures of the cytoskeletons underlying the lipid bilayer. Among various cell types, the red blood cell (RBC) possesses a relatively simple cytoskeletal structure. Underneath the membrane, the RBC cytoskeleton takes the form of a two-dimensional ...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.10.036
更新日期:2015-12-01 00:00:00
abstract::In isolated thick filaments from many types of muscle, the two head domains of each myosin molecule are folded back against the filament backbone in a conformation called the interacting heads motif (IHM) in which actin interaction is inhibited. This conformation is present in resting skeletal muscle, but it is not kn...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.06.038
更新日期:2015-08-18 00:00:00
abstract::The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other t...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2015.06.044
更新日期:2015-09-15 00:00:00
abstract::The backbone dynamics for the 29.5 kDa class A beta-lactamase PSE-4 is presented. This solution NMR study was performed using multiple field (15)N spin relaxation and amide exchange data in the EX2 regime. Analysis was carried out with the relax program and includes the Lipari-Szabo model-free approach. Showing simila...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/j.bpj.2009.02.068
更新日期:2009-06-03 00:00:00
abstract::The influence of the amino acid residues surrounding the flavin ring in the flavodoxin of the cyanobacterium Anabaena PCC 7119 on the electron spin density distribution of the flavin semiquinone was examined in mutants of the key residues Trp(57) and Tyr(94) at the FMN binding site. Neutral semiquinone radicals of the...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(99)77017-7
更新日期:1999-09-01 00:00:00
abstract::Cytosolic calcium oscillations occur in a wide variety of cells and are involved in different cellular functions. We describe these calcium oscillations by a mathematical model based on the putative electrophysiological properties of the endoplasmic reticulum (ER) membrane. The salient features of our membrane model a...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(92)81583-7
更新日期:1992-07-01 00:00:00
abstract::We report constraints on the supramolecular structure of amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (A beta(1-40)) obtained from solid-state nuclear magnetic resonance (NMR) measurements of intermolecular dipole-dipole couplings between (13)C labels at 11 carbon s...
journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(02)75244-2
更新日期:2002-08-01 00:00:00