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| Open AccessStructure of a photosynthetic reaction centre determined by serial femtosecond crystallography
Serial femtosecond crystallography is an X-ray free-electron-laser-based method that uses X-ray bursts to determine protein structures. Here the authors present the structure of a photosynthetic reaction centre, an integral membrane protein, achieved with no sign of X-ray-induced radiation damage.
- Linda C. Johansson
- , David Arnlund
- & Richard Neutze
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Functional anatomy of an allosteric protein
ϕ analysis provides a means to tease apart the dynamics of fast conformational changes in proteins by analysing the thermodynamic impact of point mutations. Purohit et al.apply this approach on a grand scale to map energy changes associated with the opening and closing of an acetylcholine receptor.
- Prasad Purohit
- , Shaweta Gupta
- & Anthony Auerbach
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A phenylalanine rotameric switch for signal-state control in bacterial chemoreceptors
Bacterial chemoreceptors regulate the kinase CheA via ligand-induced conformational changes. Using long molecular dynamics simulations, Ortega et al.show that these changes are associated with flipping of the stacked aromatic rings of highly conserved phenylalanine residues within the kinase-activating domain.
- Davi R. Ortega
- , Chen Yang
- & Igor B. Zhulin
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Article
| Open AccessMechanisms of molecular transport through the urea channel of Helicobacter pylori
Helicobacter pylori survives in the acidic environment of the stomach by taking up urea and converting it to ammonia and carbon dioxide, which buffer the bacterial periplasm. Using molecular dynamics simulations, McNulty et al. provide insight into the mechanism of urea uptake through the H. pyloriurea transporter.
- Reginald McNulty
- , Jakob P. Ulmschneider
- & Martin B. Ulmschneider
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Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics
Nck1/2 adaptor proteins control the assembly and activity of protein complexes that promote actin polymerization. Buvall et al.show that Nck1 abundance is regulated by the E3 ubiquitin ligase c-Cbl, which competes for Nck binding with the actin-binding protein synaptopodin in podocytes.
- Lisa Buvall
- , Priyanka Rashmi
- & Peter Mundel
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Article
| Open AccessHysteresis of ligand binding in CNGA2 ion channels
Cyclic nucleotide-gated channels mediate olfactory and visual responses. Using a fluorescent cGMP derivative, Nache et al.show that the rate of cyclic nucleotide release from CNGA2 depends on the extent to which this tetrameric receptor is liganded, revealing hysteresis in the gating mechanism.
- Vasilica Nache
- , Thomas Eick
- & Klaus Benndorf
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Article
| Open AccessSecondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels
Inwardly rectifying potassium channels require interactions with both PI(4,5)P2 and a second anionic phospholipid for full activation. Lee et al. locate the secondary anionic phospholipid-binding site in Kir2.1 and reveal how it synergistically promotes PI(4,5)P2sensitivity.
- Sun-Joo Lee
- , Shizhen Wang
- & Colin G. Nichols
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Characterization and modelling of interspecies electron transfer mechanisms and microbial community dynamics of a syntrophic association
Microbial community function depends on metabolic interdependencies between individual species, some of which include electron transfer. Nagarajan et al. use genomic, transcriptomic and modelling approaches to describe the mechanisms supporting the syntrophic relationship between Geobacter metallireducens and Geobacter sulfurreducens.
- Harish Nagarajan
- , Mallory Embree
- & Karsten Zengler
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From protein sequence to dynamics and disorder with DynaMine
Predicting the dynamics and disorder of a protein is a computationally complex task that, until now, has depended on prior knowledge of protein structure. Cilia et al.develop a tool to rapidly predict protein backbone dynamics based on sequence alone.
- Elisa Cilia
- , Rita Pancsa
- & Wim F. Vranken
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Equilibrium selectivity alone does not create K+-selective ion conduction in K+ channels
The preference of potassium channels to bind K+ ions over Na+ ions at equilibrium has been proposed to determine their exclusive K+ conductance. Liu and Lockless show that a related, non-selective cation channel also binds only K+ions at equilibrium, suggesting that this property alone does not determine selectivity.
- Shian Liu
- & Steve W. Lockless
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Article
| Open AccessSodium and potassium competition in potassium-selective and non-selective channels
K+ channels are selective for K+ despite the fact that Na+ can bind and conduct through the selectivity filter. Sauer et al. show that a K+-selective NaK2K channel has two high-affinity K+-binding sites, whereas a non-selective NaK2CNG channel has one, and propose a double-barrier mechanism for ion selectivity.
- David B. Sauer
- , Weizhong Zeng
- & Youxing Jiang
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Structural basis of allosteric interactions among Ca2+-binding sites in a K+ channel RCK domain
Regulator of K+ conductance (RCK) domains control the gating of potassium channels in response to ligands such as calcium. Smith et al. solve structures of the MthK RCK domain with varying numbers of calcium ions bound, and reveal the structural basis of allosteric coupling between calcium binding sites.
- Frank J. Smith
- , Victor P.T. Pau
- & Brad S. Rothberg
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Torque modulates nucleosome stability and facilitates H2A/H2B dimer loss
Histone H2A-H2B heterodimers are lost from nucleosomes during transcription by RNA polymerase II. Here Sheinin et al. investigate the behaviour of single nucleosomes subjected to DNA supercoiling and observe a loss of these heterodimers under positive supercoiling, which might have implications for histone turnover during transcription in vivo.
- Maxim Y. Sheinin
- , Ming Li
- & Michelle D. Wang
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Article
| Open AccessStructural and functional characterization of two alpha-synuclein strains
α-synuclein is implicated in neurodegenerative diseases. Bousset et al. generate two α-synuclein polymorphs and find differences in aggregation, function and toxicity, suggesting that these altered properties may be the cause for differences in disease progression.
- Luc Bousset
- , Laura Pieri
- & Ronald Melki
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Molecular determinants of common gating of a ClC chloride channel
The ClC family of chloride channels are homodimeric and contain two pores that are gated simultaneously. Bennetts and Parker combine homology modelling and mutant-cycle analysis to reveal structural linkages important for coordination of gating between subunits.
- Brett Bennetts
- & Michael W. Parker
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Article
| Open AccessRole of the C-terminal domain in the structure and function of tetrameric sodium channels
Prokaryotic voltage-gated sodium channels possess dynamically disordered cytoplasmic C-terminal domains. Bagnéris et al. present the structure of the Magnetococcus marinusNavMs pore and C-terminal domain and reveal its role in coupling channel inactivation and opening.
- Claire Bagnéris
- , Paul G. DeCaen
- & B. A. Wallace
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Srs2 prevents Rad51 filament formation by repetitive motion on DNA
Srs2 is a DNA helicase and single-stranded DNA translocase that prevents homologous recombination by dismantling Rad51 filaments. Qiu et al.use single-molecule techniques to describe Rad51 filament formation and show that Srs2 displays repetitive activity on single-stranded DNA, which prevents re-formation of Rad51 filaments after dismantling.
- Yupeng Qiu
- , Edwin Antony
- & Sua Myong
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The unusual dynamics of parasite actin result from isodesmic polymerization
Actin normally polymerizes into filaments in a cooperative manner, with nucleation and elongation phases. Skillman et al. show that actin from the protozoan parasite Toxoplasma gondiipolymerizes in an isodesmic manner, without any evidence of nucleation, resulting in filaments that are very short and unstable.
- Kristen M. Skillman
- , Christopher I. Ma
- & L. David Sibley
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Synthetic polyamines promote rapid lamellipodial growth by regulating actin dynamics
While small molecules that destabilize actin filaments are readily available, artificially stimulating actin polymerization in cells typically involves genetic manipulation. Here, the authors design cell-permeable branched polyamines that promote lamellipodium formation by stimulating actin polymerization.
- Iliana Nedeva
- , Girish Koripelly
- & Daniel Riveline
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Article
| Open AccessConformational landscapes of DNA polymerase I and mutator derivatives establish fidelity checkpoints for nucleotide insertion
The fidelity of DNA polymerases depends on conformational changes that promote the rejection of incorrect nucleotides. Here, by using an intramolecular single-molecule FRET assay, the authors establish and characterize the partially closed conformation as a crucial fidelity checkpoint.
- Johannes Hohlbein
- , Louise Aigrain
- & Achillefs N. Kapanidis
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| Open AccessThe thermodynamic patterns of eukaryotic genes suggest a mechanism for intron–exon recognition
The thermodynamics of unwinding polynucleotide duplexes can be determined from energy changes for DNA and mRNA interactions. Here the authors show that the ratio between mRNA/DNA and DNA/DNA duplex stability upstream of the 3′- spice sites is a characteristic that can contribute to intron–exon recognition.
- Marina N. Nedelcheva-Veleva
- , Mihail Sarov
- & Stoyno S. Stoynov
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| Open AccessDynamics and stoichiometry of a regulated enhancer-binding protein in live Escherichia coli cells
Cellular adaptive responses require temporal and spatial control of key regulatory protein complexes. Mehta et al. describe the dynamic interaction of a transcriptional activator mediating membrane stress response in E. coliwith its negative regulator, the cell membrane and the transcription machinery.
- Parul Mehta
- , Goran Jovanovic
- & Martin Buck
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Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis
Changes in DNA methylation during mammalian spermatogenesis are poorly understood. The authors show that the content of 5-hydroxymethylcytosine, a stable intermediate of DNA demethylation, changes dynamically during mouse spermatogenesis and is associated with functional genomic regions and transcription.
- Haiyun Gan
- , Lu Wen
- & Fuchou Tang
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Mechanistic and environmental control of the prevalence and lifetime of amyloid oligomers
Amyloid fibrils are implicated in a number of diseases but the origin of their length distributions is poorly understood. Here, evidence is presented to support a structural transition at a critical mass concentration, above which fragmentation of fibrils is suppressed.
- Ryan J. Morris
- , Kym Eden
- & Cait E. MacPhee
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| Open AccessThe pore of voltage-gated potassium ion channels is strained when closed
Voltage-gated potassium channels open and close in response to changes in transmembrane potential, but their opening mechanism is poorly understood. Here, free energy molecular dynamics simulations show that strain accumulates as the pore closes, which subsequently drives opening.
- Philip W. Fowler
- & Mark S. P. Sansom
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Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels
Dehydrated hereditary stomatocytosis is a genetic condition in which the permeability of red blood cells to cations in increased. Albuisson and colleagues find that mutations in the mechanically-activated PIEZO1 ion channel are the major cause of the disease and result in more slowly inactivating currents.
- Juliette Albuisson
- , Swetha E Murthy
- & Ardem Patapoutian
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Formin mDia1 senses and generates mechanical forces on actin filaments
Formins are a family of protein complexes that accelerate actin filament nucleation and elongation. Jegou et al.show that the formin mDia1 can generate mechanical tension in actin filaments, while conversely, pulling forces applied by viscous drag increase formin elongation activity.
- Antoine Jégou
- , Marie-France Carlier
- & Guillaume Romet-Lemonne
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Transcription factor binding kinetics constrain noise suppression via negative feedback
Live cell imaging have recently revealed that transcription factors spend up to 4 min to find and bind their chromosomal binding site. Grönlund et al. show that this slow search process leads to tradeoffs between strength and speed of negative autoregulation for effective noise suppression.
- Andreas Grönlund
- , Per Lötstedt
- & Johan Elf
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| Open AccessALKBH4-dependent demethylation of actin regulates actomyosin dynamics
The division of a single eukaryotic cell into two requires actomyosin-dependent contraction. Here the authors show that lysine methylation of actin inhibits contractility during cytokinesis by blocking its association with myosin, and this modification is reversed at the contractile ring by the demethylase ALKBH4.
- Ming-Ming Li
- , Anja Nilsen
- & Yun-Gui Yang
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| Open AccessA novel mechanism for fine-tuning open-state stability in a voltage-gated potassium channel
Voltage-gated potassium channels cycle between closed and open states through poorly-defined transitions. Pless and colleagues incorporate artificial amino acids into Shaker potassium channels and find that that the negative electrostatic surface potential of Phe481, destabilizes the channel open state.
- Stephan A. Pless
- , Ana P. Niciforovic
- & Christopher A. Ahern
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Article
| Open AccessThe four-transmembrane protein IP39 of Euglena forms strands by a trimeric unit repeat
IP39 is an abundant protozoan protein known to form highly-ordered striations in Euglena gracilis’ plasma membrane. Here, Suzuki et al. determine its three-dimensional structure by electron crystallography revealing that IP39 polymerises to form trimeric longitudinal units arranged in a molecular strand of antiparallel double-rows.
- Hiroshi Suzuki
- , Yasuyuki Ito
- & Sachiko Tsukita
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A light-driven sodium ion pump in marine bacteria
Light-driven proton-pumping rhodopsins are widely distributed in microorganisms and convert sunlight energy into proton gradients. Inoue et al. report the discovery of a light-driven sodium ion pump from marine bacteria.
- Keiichi Inoue
- , Hikaru Ono
- & Hideki Kandori
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Biased Brownian stepping rotation of FoF1-ATP synthase driven by proton motive force
The visualization of ion-motive-force driven conformational dynamics of membrane proteins is hampered by technical difficulties. Here, the authors develop an experimental platform to visualize the rotary dynamics of ATP synthase driven by proton-motive-force.
- Rikiya Watanabe
- , Kazuhito V. Tabata
- & Hiroyuki Noji
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Probing transcription factor diffusion dynamics in the living mammalian embryo with photoactivatable fluorescence correlation spectroscopy
Transcription factor diffusion along DNA regulates many fundamental cellular and developmental processes. Kaur et al. combine photoactivation and fluorescence correlation spectroscopy to investigate transcription factor diffusion in mouse embryos and show that diffusion kinetics change during cell differentiation.
- Gurpreet Kaur
- , Mauro W. Costa
- & Nicolas Plachta
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CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire
Cullin 1-RING ubiquitin ligase complexes interact with a wide variety of substrates by recruiting different substrate receptor subunits. Here the authors demonstrate that CAND1 promotes rapid exchange of substrate receptors, thus ensuring comprehensive sampling of the entire repertoire.
- Shuangding Wu
- , Wenhong Zhu
- & Dieter A. Wolf
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| Open AccessDisease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface
Ryanodine receptors are calcium-release channels located in the membrane of the sarcoplasmic and endoplasmic reticulum. Kimlicka et al.compare pseudo-atomic models of the N-terminal area in the open and closed states and characterize the mutations in the N-terminal that disrupt channel opening.
- Lynn Kimlicka
- , Kelvin Lau
- & Filip Van Petegem
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| Open AccessReal-time single-molecule co-immunoprecipitation analyses reveal cancer-specific Ras signalling dynamics
Co-immunoprecipitation provides static and qualitative information about protein–protein interactions. Lee et al.create real-time movies of single protein–protein interactions during co-immunoprecipitation, and use them to assess the dynamics of mutant Ras proteins derived from tumours.
- Hong-Won Lee
- , Taeyoon Kyung
- & Tae-Young Yoon
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Mechanism of tetracycline resistance by ribosomal protection protein Tet(O)
The bacterial tetracycline resistance protein Tet(O) binds to the ribosome, preventing tetracycline from inhibiting translation. Using cryo-electron microscopic reconstruction, the authors present an atomic model of Tet(O) bound to the 70S ribosome, and reveal how Tet(O) promotes antibiotic resistance.
- Wen Li
- , Gemma C. Atkinson
- & Joachim Frank
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Article
| Open AccessInterplay between myosin IIA-mediated contractility and actin network integrity orchestrates podosome composition and oscillations
Dendritic cells use protrusive structures called podosomes to probe the extracellular environment. Here the authors reveal how interplay between actin-mediated core growth and myosin-mediated tension regulates podosome protrusion.
- K. van den Dries
- , M.B.M Meddens
- & A. Cambi
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Non-uniform membrane diffusion enables steady-state cell polarization via vesicular trafficking
The mechanism by which proteins become polarized to a specific cortical site in budding yeast cells has been a topic of recent debate. Slaughter et al.show that differing diffusion rates of Cdc42 within plasma membrane environments sustain the polarized state.
- Brian D. Slaughter
- , Jay R. Unruh
- & Rong Li
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Evolution of the protein stoichiometry in the L12 stalk of bacterial and organellar ribosomes
The ribosomal stalk L12 is the only multi-copy protein in the ribosome and is essential for translation. Here Davydov et al.use a bioinformatics and mass spectrometry approach to study the evolution of L12 in bacterial ribosomes and predict its stoichiometry in a wide range of species.
- Iakov I. Davydov
- , Ingo Wohlgemuth
- & Marina V. Rodnina
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| Open AccessMultiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel
In outwardly rectifying potassium channels, depolarization initiates conformational changes in voltage-sensing domains. Goldschen-Ohmet al. find that movement of three specific domains correlates with conductance levels, and rearrangements of a fourth domain results in preinactivation subconductance states.
- Marcel P. Goldschen-Ohm
- , Deborah L. Capes
- & Baron Chanda
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Article
| Open AccessStructural insights into protein-only RNase P complexed with tRNA
RNase P is a key enzyme implicated in transfer RNA maturation that removes the 5′-leader sequences from transfer RNA precursors. In this study, a biophysical characterization of a novel protein-only variant of RNase P, known as PRORP (PROteinaceous RNase P), reveals that transfer RNA recognition by PRORP is similar to that by ribonucleoprotein RNase P.
- Anthony Gobert
- , Franziska Pinker
- & Philippe Giegé
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Molecular mechanism of the assembly of an acid-sensing receptor ion channel complex
Polycystic kidney disease family proteins form heteromeric complexes with transient receptor potential channel subunits of the TRPP subfamily. Yu and colleagues find that the polycystic kidney disease protein, PKD1L3, is an ion channel pore-forming subunit in the acid-sensing PKD1L3/TRPP3 complex.
- Yong Yu
- , Maximilian H. Ulbrich
- & Jian Yang
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Article
| Open AccessLocalizing internal friction along the reaction coordinate of protein folding by combining ensemble and single-molecule fluorescence spectroscopy
Internal friction affects the kinetics of protein folding. Borgiaet al. investigate how this friction affects the folding dynamics of the protein spectrin, revealing a potential role in the rate-limiting conformational changes.
- Alessandro Borgia
- , Beth G. Wensley
- & Benjamin Schuler
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Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel
Mutations of the NaV1.7 voltage-gated sodium channel are implicated in abnormal pain signal transduction. Yang and colleagues perform structural modeling, mutant cycle analysis and electrophysiology on specific mutants and find that they can accurately predict their response profiles to channel blockers.
- Yang Yang
- , Sulayman D. Dib-Hajj
- & Stephen G. Waxman
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Cobweb-weaving spiders produce different attachment discs for locomotion and prey capture
Spider webs consist of scaffolding silk, which supports the cobweb, and gumfoot silk, which can detach easily from the web upon contact with prey. Here, these different mechanical demands are shown to be met by silk attachments of two distinct architectures using the same pyriform silk secretions.
- Vasav Sahni
- , Jared Harris
- & Ali Dhinojwala
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Article
| Open AccessStructure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing
Sodium-gated ion channels open and close in response to the flow of ions. Here, McCusker et al.report the open structure of a sodium-gated ion channel pore from a bacterial homologue, and show, by comparison with the closed structure, that the movement of a C-terminal helix is sufficient to open the channel.
- Emily C. McCusker
- , Claire Bagnéris
- & B.A. Wallace
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Article
| Open AccessEfficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region
Many drugs exist that target the β-adrenergic receptor, but they have different efficacies. Kofukuet al. use NMR to show that methionine 82 in the transmembrane domain undergoes conformational changes depending on whether agonists or inverse agonists are bound, explaining the differential drug efficacy.
- Yutaka Kofuku
- , Takumi Ueda
- & Ichio Shimada