The metabotropic glutamate receptors (mGluRs) are key receptors in the modulation of excitatory synaptic transmission in the central nervous system. Here we have determined three different crystal structures of the extracellular ligand-binding region of mGluR1--in a complex with glutamate and in two unliganded forms. They all showed disulphide-linked homodimers, whose 'active' and 'resting' conformations are modulated through the dimeric interface by a packed alpha-helical structure. The bi-lobed protomer architectures flexibly change their domain arrangements to form an 'open' or 'closed' conformation. The structures imply that glutamate binding stabilizes both the 'active' dimer and the 'closed' protomer in dynamic equilibrium. Movements of the four domains in the dimer are likely to affect the separation of the transmembrane and intracellular regions, and thereby activate the receptor. This scheme in the initial receptor activation could be applied generally to G-protein-coupled neurotransmitter receptors that possess extracellular ligand-binding sites.

We consider a model of Dirac fermions in 2+1 dimensions with dynamically generated, anticommuting SO(3) Néel and Z_{2} Kekulé mass terms that permits sign-free quantum Monte Carlo simulations. The phase diagram is obtained from finite-size scaling and includes a direct and continuous transition between the Néel and Kekulé phases. The fermions remain gapped across the transition, and our data support an emergent SO(4) symmetry unifying the two order parameters. While the bare symmetries of our model do not allow for spinon-carrying Z_{3} vortices in the Kekulé mass, the emergent SO(4) invariance permits an interpretation of the transition in terms of deconfined quantum criticality. The phase diagram also features a tricritical point at which the Néel, Kekulé, and semimetallic phases meet. The present sign-free approach can be generalized to a variety of other mass terms and thereby provides a new framework to study exotic critical phenomena.

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The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug.

Previously, we determined the crystal structures of the dimeric ligand binding region of the metabotropic glutamate receptor subtype 1. Each protomer binds Lglutamate within the crevice between the LB1 and LB2 domains. We proposed that the two different conformations of the dimer interface between the two LB1 domains define the activated and resting states of the receptor protein. In this study, the residues in the ligandbinding site and the dimer interface were mutated, and the effects were analyzed in the full-length and truncated soluble receptor forms. The variations in the ligand binding activities of the purified truncated receptors are comparable with those of the full-length form. The mutated full-length receptors were also analyzed by inositol phosphate production and Ca 2؉ response. , and Gly 293 residues, which interact with the ␥-carboxyl group of glutamate, lost their responsiveness to glutamate but not to quisqualate. Furthermore, a mutant receptor containing alanine instead of isoleucine at position 120 located within an ␣ helix constituting the dimer interface showed no intracellular response to ligand stimulation. The results demonstrate the crucial role of the dimer interface in receptor activation.Glutamate is a major neurotransmitter in excitatory neurons in the central nervous system. Glutamate released into the synaptic space is recognized by two distinct receptors, glutamate-gated ion channels and metabotropic glutamate receptors (mGluRs) 1 (1, 2). The mGluRs consist of eight subtypes (mGluR1 to -8), which couple with a variety of effector systems, including inositol phosphate pathway, adenylyl cyclase, ion channels, etc. The mGluRs are considered to modulate synaptic neurotransmission and thus to play roles in memory, learning, and brain disorders such as epilepsy and neurodegenerative diseases.The mGluR consists of three regions: a large extracellular region, a seven-transmembrane-spanning region, and an intracellular region. Previously, we determined the crystal structures of the extracellular ligand-binding region (LBR) of mGluR1 (3). In combination with biochemical studies (4, 5), the mGluR1-LBR (m1-LBR) was found to be a homodimer consisting of two protomers. Each protomer consists of an LB1 domain and an LB2 domain. The glutamate-binding structure is a dimer composed of closed and open protomers, which differ in the relative orientation of the LB1 and LB2 domains. Without glutamate, two crystal forms of m1-LBR were obtained; one form exists as an open-open dimer, and the other is an openclosed form. The two main functioning sites were then elucidated: the ligand-recognition site and the LB1 dimer interface. In the ligand binding site, glutamate interacts mainly with 13 amino acid residues from the LB1 and LB2 domains of the protomer. We proposed that the ligand-binding domain of mGluR1 is in dynamic equilibrium between the activated state and the resting state, which are defined mainly by the different dimer interface conformations of the three crystal forms. An antagonist binding c...

The discovery of quantum spin-Hall (QSH) insulators has brought topology to the forefront of condensed matter physics. While a QSH state from spin-orbit coupling can be fully understood in terms of band theory, fascinating many-body effects are expected if it instead results from spontaneous symmetry breaking. Here, we introduce a model of interacting Dirac fermions where a QSH state is dynamically generated. Our tuning parameter further allows us to destabilize the QSH state in favour of a superconducting state through proliferation of charge-2e topological defects. This route to superconductivity put forward by Grover and Senthil is an instance of a deconfined quantum critical point (DQCP). Our model offers the possibility to study DQCPs without a second length scale associated with the reduced symmetry between field theory and lattice realization and, by construction, is amenable to large-scale fermion quantum Monte Carlo simulations.

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Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G, referred to here as A3G) is a potent antiretroviral host factor against human immunodeficiency virus type 1 (HIV-1). HIV-1 viral infectivity factor (Vif) counteracts A3G by promoting its degradation via the ubiquitin-proteasome pathway. Recent studies demonstrated that protein kinase A (PKA) phosphorylates activation-induced deaminase (AID), another member of the APOBEC3 family. A3G has two putative PKA phosphorylation residues. Here we show that PKA binds and specifically phosphorylates A3G at Thr32 in vitro and in vivo. This phosphorylation event reduces the binding of A3G to Vif and its subsequent ubiquitination and degradation, and thus promotes A3G antiviral activity. Computer-assisted structural modeling and mutagenesis studies suggest that the interaction between A3G Thr32 and Arg24 is crucial for interaction with Vif. These data imply that PKA-mediated phosphorylation of A3G can regulate the interaction between A3G and Vif.