The spike glycoprotein (S) of recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) targets the cellular receptor, dipeptidyl peptidase 4 (DPP4). Sequence comparison and modeling analysis have revealed a putative receptor-binding domain (RBD) on the viral spike, which mediates this interaction. We report the 3.0 Å-resolution crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4. Our results show that MERS-CoV RBD consists of a core and a receptor-binding subdomain. The receptor-binding subdomain interacts with DPP4 β-propeller but not its intrinsic hydrolase domain. MERS-CoV RBD and related SARS-CoV RBD share a high degree of structural similarity in their core subdomains, but are notably divergent in the receptor-binding subdomain. Mutagenesis studies have identified several key residues in the receptor-binding subdomain that are critical for viral binding to DPP4 and entry into the target cell. The atomic details at the interface between MERS-CoV RBD and DPP4 provide structural understanding of the virus and receptor interaction, which can guide development of therapeutics and vaccines against MERS-CoV infection.

Interleukin 1β (IL-1β) is a key orchestrator of inflammation and host defense that exerts its effects through IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP). How IL-1RAcP is recruited by IL-1β-IL-1RI to form the signaling-competent complex remains elusive. Here we present the crystal structure of IL-1β bound to IL-1 receptor type II (IL-1RII) and IL-1RAcP. IL-1β-IL-1RII generated a composite binding surface to recruit IL-1RAcP. Biochemical analysis demonstrated that IL-1β-IL-1RI and IL-1β-IL-1RII interacted similarly with IL-1RAcP. It also showed the importance of two loops of IL-1 receptor antagonist (IL-1Ra) in determining its antagonism. Our results provide a structural basis for assembly and activation of the IL-1 receptor and offer a general cytokine-receptor architecture that governs the IL-1 family of cytokines.

Halogenated contaminants, particularly brominated flame retardants, disrupt circulating levels of thyroid hormones (THs), potentially affecting growth and development. Disruption may be mediated by impacts on deiodinase (DI) activity, which regulate the levels of active hormones available to bind to nuclear receptors. The goal of this study was to develop a mass spectrometry-based method for measuring the activity of DIs in human liver microsomes and to examine the effect of halogenated phenolic contaminants on DI activity. Thyroxine (T4) and reverse triiodothyronine (rT3) deiodination kinetics were measured by incubating pooled human liver microsomes with T4 or rT3 and monitoring the production of T3, rT3, 3,3'-diiodothyronine, and 3-monoiodothyronine by liquid chromatography tandem mass spectrometry. Using this method, we examined the effects of several halogenated contaminants, including 2,2',4,4',5-pentabromodiphenyl ether (BDE 99), several hydroxylated polybrominated diphenyl ethers (OH-BDEs), tribromophenol, tetrabromobisphenol A, and triclosan, on DI activity. The Michaelis constants (K(M)) of rT3 and T4 deiodination were determined to be 3.2 ± 0.7 and 17.3 ± 2.3μM. The V(max) was 160 ± 5.8 and 2.8 ± 0.10 pmol/min.mg protein, respectively. All studied contaminants inhibited DI activity in a dose-response manner, with the exception of BDE 99 and two OH-BDEs. 5'-Hydroxy 2,2',4,4',5-pentabromodiphenyl ether was found to be the most potent inhibitor of DI activity, and phenolic structures containing iodine were generally more potent inhibitors of DI activity relative to brominated, chlorinated, and fluorinated analogues. This study suggests that some halogenated phenolics, including current use compounds such as plastic monomers, flame retardants, and their metabolites, may disrupt TH homeostasis through the inhibition of DI activity in vivo.

The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-proteincoupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family.

Soil and sediment collected in the vicinity of an open electronic waste disposal and recycling facility located in Guiyu, Guangdong, China, were analyzed for the levels of common polybrominated diphenyl ethers (PBDEs) by using soxhlet extraction and gas chromatography/mass spectrometry. The PBDEs were detected in the soil and sediment samples at levels of 0.26-824 ng/g (dry weight). The obtained isomer profiles of PBDEs from the two soil samples collected from different contamination sites were found to be similar to various technical formulations of fire retardant products.