Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. ...Despite the substantial progression of our structural understanding of GPCR activation by small molecule and peptide agonists, the molecular mechanism of GPCR activation by protein agonists remains unclear. Here, we present a 3.3-Å cryo-electron microscopy structure of the human chemokine receptor CCR6 bound to its endogenous ligand CCL20 and an engineered Go. CCL20 binds in a shallow extracellular pocket, making limited contact with the core 7-transmembrane (TM) bundle. The structure suggests that this mode of binding induces allosterically a rearrangement of a noncanonical toggle switch and the opening of the intracellular crevice for G protein coupling. Our results demonstrate that GPCR activation by a protein agonist does not always require substantial interactions between ligand and the 7TM core region.
The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It ...is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein–coupled receptors (GPCRs). We determined the ...structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights about the allosteric modulation and activation mechanism of class C GPCRs.
Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of κ-opioid ...receptor (κ-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. ...Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Effects of ballast water treatment by advanced electro-catalysis oxidation processes (AEOP) on abundance, activity, and diversity of marine bacteria were examined in a full-scale ballast ...water management system (BWMS) at Yangshan Port, Shanghai, China. Water samples were collected immediately after treatment and at discharge to evaluate the contingency treatment performance of the BWMS for bacteria. After treatment, the total viable count reduced to 0.7 × 104 CFU·mL−1, and both Escherichia coli and enterococci decreased to 10 CFU·100 mL−1, which satisfied the D-2 Standard of the International Maritime Organization. AEOP can be as an effective contingency reception facility. Sequencing of 16S rRNA gene amplicons demonstrated the declining trend in bacterial diversity, and while the treatment did not completely eliminate the risk of bacterial dispersal, potentially pathogenic bacteria survived in treated and discharged samples. Bacterial diversity is of greater concern when evaluating effects of ballast water treatment on microorganisms because the bacteria which can develop adaptive mechanisms to environmental change will have a greater potential for invasion in the new environment.
In recent years, the issue of invasive alien species brought on by ballast water has drawn increasing attention, and advances in ballast water treatment technologies have been made. One of the most ...popular combined ballast water treatment technologies utilized in ballast water management systems (BWMSs) globally is filtration + UV-C radiation. During the actual voyage of the ship, ballast water is treated by the BWMS and then enters the dark ballast tanks until the ballast water is discharged. Marine organisms are able to complete DNA damage caused by UV radiation in dark ballast tanks. Therefore, the length of holding time affects the effectiveness of the BWMS in treating ballast water. The objective of this study was to examine the efficacy of filtration + UV-C irradiation treatment at different holding times for the removal or inactivation of phytoplankton and zooplankton populations during simulated ballast water treatment. Results indicate that the holding time after the filtration + UV-C radiation treatment increased the inactivating efficacy, especially for zooplankton in natural seawater. For phytoplanktons in ballast water, the strongest impact on the treatment efficacy was reached with a holding time of 24 h.
Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT 1B G protein–coupled ...receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT 2B receptor, the 5-HT 1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.
The worst-case linear optimization (WCLO) with uncertainties in the right-hand-side of the constraints often arises from numerous applications such as systemic risk estimate in finance and stochastic ...optimization, which is known to be NP-hard. In this paper, we investigate the efficient global algorithm for WCLO based on its nonlinear semidefinite relaxation (SDR). We first derive an enhanced nonlinear SDR for WCLO via secant cuts and RLT approaches. A secant search algorithm is then proposed to solve the nonlinear SDR and its global convergence is established. Second, we propose a new global algorithm for WCLO, which integrates the nonlinear SDR with successive convex optimization method, initialization and branch-and-bound, to find a globally optimal solution to the underlying WCLO within a pre-specified
ϵ
-tolerance. We establish the global convergence of the algorithm and estimate its complexity. Preliminary numerical results demonstrate that the proposed algorithm can effectively find a globally optimal solution to the WCLO instances.
Chelydra serpentina (Linnaeus, 1758) is native to North America, but has been introduced to numerous nations and is now globally spread. It is extremely adaptive, grow quickly, and its biological ...population is steadily increasing as a result of the development of aquaculture technology. Given that Chelydra serpentina has already been found alive in the natural ecosystems of China, its proliferation poses a possible threat of invasion. Using the global distribution data of the species in the current environment, a study was carried out to forecast the distribution trend of Chelydra serpentina under future climate circumstances. The study compared the changes in the distribution area under current climatic circumstances and the tendency of proliferation using 19 bioclimatic factors and the ecological niche model Maxent. Using the significance index, the study also examined the size of the appropriate region and the influencing factors to estimate the danger of Chelydra serpentina invasion better quantitatively. In our research, we hypothesized that forthcoming climate change will affect the geographical distribution of Chelydra serpentina. The study results showed that, even in high-intensity environments, the appropriate area for Chelydra serpentina will steadily increase in the future climate. The extent of their suitable habitat might expand (the highly suitable area: 7.42*105 km2 ; 2.13*107 km2 ) in contrast to the distribution area of Chelydra serpentina under the existing climate (highly suitable area: 6.01*105 km2 ; 8.48*106 km2 ). The research findings indicate that the range of the habitat area predicted to proliferate (the highly suitable area of 6.31*105 km2 ; 1.3 *107 km2 ) even in high-intensity environments, albeit at a slower rate than in the low-intensity environment model. The habitat will initially be concentrated in warmer regions before progressively expanding into the colder northern climate. This implies that Chelydra serpentina will be able to more easily adjust to future climates and spread outward over time from its concentrated home. Nonetheless, there is a chance of an invasion due to the rise in Chelydra serpentina populations. Upon establishing a regular reproductive presence in the Chinese waterways they inhabit, these turtles will engage in fierce competition with indigenous species for survival, posing a threat to the environment and potentially resulting in the extinction of some local species.
•Global spread and proliferation trends of Chelydra serpentina.•Impact of climate change on distribution areas of Chelydra serpentina.•Significant habitat expansion by Chelydra serpentina.•Chelydra serpentina may expand to colder northern regions, posing unknown impacts on ecosystems.•Quantitative assessment of invasion risk.
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