The nuclear receptor PPARgamma/RXRalpha heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazolidinediones (TZDs). We report the crystal structures of the PPARgamma and RXRalpha LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PPARgamma agonist rosiglitazone or GI262570, and coactivator peptides. The PPARgamma/RXRalpha heterodimer is asymmetric, with each LBD deviated approximately 10 degrees from the C2 symmetry, allowing the PPARgamma AF-2 helix to interact with helices 7 and 10 of RXRalpha. The heterodimer interface is composed of conserved motifs in PPARgamma and RXRalpha that form a coiled coil along helix 10 with additional charge interactions from helices 7 and 9. The structures provide a molecular understanding of the ability of RXR to heterodimerize with many nuclear receptors and of the permissive activation of the PPARgamma/RXRbeta heterodimer by 9cRA.
The first crystal structure of human cyclooxygenase-2, in the presence of a selective inhibitor, is similar to that of cyclooxygenase-1. The structure of the NSAID binding site is also well conserved, although there are differences in its overall size and shape which may be exploited for the further development of selective COX-2 inhibitors. A second COX-2 structure with a different bound inhibitor displays a new, open conformation at the bottom of the NSAID binding site, without significant changes in other regions of the COX-2 structure. These two COX-2 structures provide evidence for the flexible nature of cyclooxygenase, revealing details about how substrate and inhibitor may gain access to the cyclooxygenase active site from within the membrane.
BackgroundHuman activities have increased atmospheric concentrations of carbon dioxide by 36% during the past 200 years. One third of all anthropogenic CO2 has been absorbed by the oceans, reducing pH by about 0.1 of a unit and significantly altering their carbonate chemistry. There is widespread concern that these changes are altering marine habitats severely, but little or no attention has been given to the biota of estuarine and coastal settings, ecosystems that are less pH buffered because of naturally reduced alkalinity.Methodology/Principal FindingsTo address CO2-induced changes to estuarine calcification, veliger larvae of two oyster species, the Eastern oyster (Crassostrea virginica), and the Suminoe oyster (Crassostrea ariakensis) were grown in estuarine water under four pCO2 regimes, 280, 380, 560 and 800 µatm, to simulate atmospheric conditions in the pre-industrial era, present, and projected future concentrations in 50 and 100 years respectively. CO2 manipulations were made using an automated negative feedback control system that allowed continuous and precise control over the pCO2 in experimental aquaria. Larval growth was measured using image analysis, and calcification was measured by chemical analysis of calcium in their shells. C. virginica experienced a 16% decrease in shell area and a 42% reduction in calcium content when pre-industrial and end of 21st century pCO2 treatments were compared. C. ariakensis showed no change to either growth or calcification. Both species demonstrated net calcification and growth, even when aragonite was undersaturated, a result that runs counter to previous expectations for invertebrate larvae that produce aragonite shells.Conclusions and SignificanceOur results suggest that temperate estuarine and coastal ecosystems are vulnerable to the expected changes in water chemistry due to elevated atmospheric CO2 and that biological responses to acidification, especially calcifying biota, will be species-specific and therefore much more variable and complex than reported previously.
The 2.7 A X-ray crystal structure of the HNF4gamma ligand binding domain (LBD) revealed the presence of a fatty acid within the pocket, with the AF2 helix in a conformation characteristic of a transcriptionally active nuclear receptor. GC/MS and NMR analysis of chloroform/methanol extracts from purified HNF4alpha and HNF4gamma LBDs identified mixtures of saturated and cis-monounsaturated C14-18 fatty acids. The purified HNF4 LBDs interacted with nuclear receptor coactivators, and both HNF4 subtypes show high constitutive activity in transient transfection assays, which was reduced by mutations designed to interfere with fatty acid binding. The endogenous fatty acids did not readily exchange with radiolabeled palmitic acid, and all attempts to displace them without denaturing the protein failed. Our results suggest that the HNF4s may be transcription factors that are constitutively bound to fatty acids.
X-ray crystal structures of the ligand binding domain (LBD) of the estrogen-related receptor-␥ (ERR␥) were determined that describe this receptor in three distinct states: unliganded, inverse agonist bound, and agonist bound. Two structures were solved for the unliganded state, the ERR␥ LBD alone, and in complex with a coregulator peptide representing a portion of receptor interacting protein 140 (RIP140). No significant differences were seen between these structures that both exhibited the conformation of ERR␥ seen in studies with other coactivators. Two structures were obtained describing the inverse agonist-bound state, the ERR␥ LBD with 4-hydroxytamoxifen (4-OHT), and the ERR␥ LBD with 4-OHT and a peptide representing a portion of the silencing mediator of retinoid and thyroid hormone action protein (SMRT). The 4-OHT structure was similar to other reported inverse agonist bound structures, showing reorientation of phenylalanine 435 and a displacement of the AF-2 helix relative to the unliganded structures with little other rearrangement occurring. No significant changes to the LBD appear to be induced by peptide binding with the addition of the SMRT peptide to the ERR␥ plus 4-OHT complex. The observed agonist-bound state contains the ERR␥ LBD, a ligand (GSK4716), and the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding residues. Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. In contrast to the conventional mechanism of nuclear receptor ligand activation, activation of ERR␥ by GSK4716 does not appear to involve a major rearrangement or significant stabilization of the C-terminal helix. The nuclear receptor (NR)2 superfamily comprises 48 ligand-regulated transcription factors in the human genome.Amino acid sequence alignment identifies several conserved regions within the NRs: a central, highly conserved DNA binding domain that allows for the sequence-specific recognition of DNA in the promoter region of the genes; a C-terminal ligand binding domain (LBD) that is able to bind small, lipophilic molecules and influence the interaction with cofactors involved in transcriptional regulation; and a poorly conserved N-terminal domain. X-ray crystallography has revealed that the canonical NR LBD is composed of 10 -13 ␣-helices arranged in a three-layered sandwich, the interior of which varies in volume and functional character to define the molecular basis of ligand specificity.The estrogen-related receptors (ERR␣, ERR, and ERR␥, or NR3B1, NR3B2, and NR3B3, respectively) define a subfamily of three orphan NRs most closely related to the classic estrogen receptors (ER␣ and ER). Because of high sequence conservation within the DNA binding domains of the two subfamilies, the classic ERs and orphan ERRs are able to recognize common DNA binding sites (also known as response elements) proximal to target genes (1). For example, the orphan ERRs have demonstrated control over classic ER target genes in breast (2) and bone (3). Althou...
The North Atlantic intertidal gastropod, Littorina saxatilis (Olivi, 1792), exhibits extreme morphological variation between and within geographic regions and has become a model for studies of local adaptation; yet a comprehensive analysis of the species' phylogeography is lacking. Here, we examine phylogeographic patterns of the species' populations in the North Atlantic and one remote Mediterranean population using sequence variation in a fragment of the mitochondrial cytochrome b gene (607 bp). We found that, as opposed to many other rocky intertidal species, L. saxatilis has likely had a long and continuous history in the Northwest Atlantic, including survival during the last glacial maximum (LGM), possibly in two refugia. In the Northeast Atlantic, several areas likely harboured refugial populations that recolonized different parts of this region after glacial retreat, resulting in strong population structure. However, the outlying monomorphic Venetian population is likely a recent anthropogenic introduction from northern Europe and not a remnant of an earlier wider distribution in the Mediterranean Sea. Overall, our detailed phylogeography of L. saxatilis adds an important piece to the understanding of Pleistocene history in North Atlantic marine biota as well as being the first study to describe the species' evolutionary history in its natural range. The latter contribution is noteworthy because the snail has recently become an important model species for understanding evolutionary processes of speciation; thus our work provides integral information for such endeavours.
Rising atmospheric CO2 often triggers the production of plant phenolics, including many that serve as herbivore deterrents, digestion reducers, antimicrobials, or ultraviolet sunscreens. Such responses are predicted by popular models of plant defense, especially resource availability models which link carbon availability to phenolic biosynthesis. CO2 availability is also increasing in the oceans, where anthropogenic emissions cause ocean acidification, decreasing seawater pH and shifting the carbonate system towards further CO2 enrichment. Such conditions tend to increase seagrass productivity but may also increase rates of grazing on these marine plants. Here we show that high CO2 / low pH conditions of OA decrease, rather than increase, concentrations of phenolic protective substances in seagrasses and eurysaline marine plants. We observed a loss of simple and polymeric phenolics in the seagrass Cymodocea nodosa near a volcanic CO2 vent on the Island of Vulcano, Italy, where pH values decreased from 8.1 to 7.3 and pCO2 concentrations increased ten-fold. We observed similar responses in two estuarine species, Ruppia maritima and Potamogeton perfoliatus, in in situ Free-Ocean-Carbon-Enrichment experiments conducted in tributaries of the Chesapeake Bay, USA. These responses are strikingly different than those exhibited by terrestrial plants. The loss of phenolic substances may explain the higher-than-usual rates of grazing observed near undersea CO2 vents and suggests that ocean acidification may alter coastal carbon fluxes by affecting rates of decomposition, grazing, and disease. Our observations temper recent predictions that seagrasses would necessarily be “winners” in a high CO2 world.
The observed rates and deleterious impacts of biological invasions have caused significant alarm in recent years, driving efforts to reduce the risk (establishment) of new introductions. Characterizing the supply of propagules is key to understanding invasion risk and developing effective management strategies. In coastal ecosystems, ships' ballast water is an important transfer mechanism (vector) for marine and freshwater species. Commercial ships exhibit a high degree of variation in ballast water operations that affect both the quantity and quality of propagule supply, and thereby invasion risk. The per-ship inoculation size from ballast water depends upon both the volume discharged and the organism density. Moreover, propagule quality will vary among source regions (ports) and voyage routes, due to differences in species composition and transport conditions, respectively. We show that significant differences exist in (i) the frequency and volume of ballast water discharge among vessel types, (ii) the frequency of vessel types and routes (source regions) among recipient ports, and (iii) the transit success (survivorship) of zooplankton in ballast tanks among voyage routes. Thus, propagule supply is not a simple function of total ship arrivals. For ships, as well as other vectors, variation in propagule quantity and quality must be explicitly considered to estimate invasion risk and advance predictive ability.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.