Highlightsand CB2-AM12033 are determined d Structural evidence of G protein selectivity by CB1 and CB2 is identified d MD simulations reveal the distinct binding behavior of HU308 in CB2 and CB1 d Cholesterol molecule as an endogenous allosteric modulator of CB1 is uncovered

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.

Kapton polyimde is extensively used in solar arrays, spacecraft thermal blankets, and space inflatable structures. Upon exposure to atomic oxygen in low Earth orbit (LEO), Kapton is severely eroded. An effective approach to prevent this erosion is to incorporate polyhedral oligomeric silsesquioxane (POSS) into the polyimide matrix by copolymerizing POSS monomers with the polyimide precursor. The copolymerization of POSS provides Si and O in the polymer matrix on the nano level. During exposure of POSS polyimide to atomic oxygen, organic material is degraded, and a silica passivation layer is formed. This silica layer protects the underlying polymer from further degradation. Laboratory and space-flight experiments have shown that POSS polyimides are highly resistant to atomic-oxygen attack, with erosion yields that may be as little as 1% those of Kapton. The results of all the studies indicate that POSS polyimide would be a space-survivable replacement for Kapton on spacecraft that operate in the LEO environment.

Supporting Information 1 Characterization of Instrument Effects using NO2 PhotolysisExperiments measuring the instrument response function (IRF) used a certified mix of NO2 in He (Matheson Tri-Gas, 1.00% NO2 with 0.5% O2 as a stabilizing agent in He). We conducted NO2 photolysis experiments at 8 Torr and 10.0 eV photon energy. The NO + and NO2 + signals are shown in Figure S1. Following photolysis at t = 0, we observed a small depletion in the NO2 + and a fast rise in the NO + signal. The measured depletion of NO2 (from both photolytic and kinetic reactions) was 4.6 ± 0.5% determined by fitting the data over the time range from −20 to 20 ms. At later 1

The chemical bonding and morphology of chemical vapor deposited (CVD) diamond films exposed to thermal (∼0.04 eV) and hyperthermal (5 and 7.5 eV) atomic oxygen (AO) were studied by using high resolution electron energy loss spectroscopy (HREELS), atomic force microscopy, and theoretical simulations. Although exposure to thermal AO caused subtle changes to the surface morphology, hyperthermal AO resulted in selective etching of the diamond facets: (100) facets remained essentially unaffected, whereas (111)-oriented and other facets were severely etched. HREELS reveals that hydrogen is removed from the diamond surfaces during both thermal and hyperthermal AO exposures. By using isotopic labeling in the CVD growth procedure, it is observed that exposure to ambient conditions after the AO exposure leads to adsorption of adventitious hydrocarbons on the surface. The high background in the HREEL spectrum of samples exposed to hyperthermal AO suggests the presence of a graphitic layer. Simulations of the interaction between hyperthermal AO and (100) and (111) diamond surfaces were conducted by using direct dynamics based on density-functional-based tight binding methods, in an attempt to elucidate relevant reaction mechanisms. They suggest mechanisms for the partial graphitization of the (111) surface and for etching of this surface by way of CO2 desorption. Such damaged graphitic layers have been previously shown to erode easily when exposed to a hyperthermal AO beam. The simulations also suggest that the (100) surface, fully covered with ketones, is inert to carbon removal upon exposure to hyperthermal oxygen atoms, which scatter inelastically from this surface without reaction. The simulations suggest that a nearly full ketone coverage is the steady-state configuration for a (100) diamond surface exposed to AO.

Recent measurements of methane (CH4) by the Mars Science Laboratory (MSL) now confront us with robust data that demand interpretation. Thus far, the MSL data have revealed a baseline level of CH4 (∼0.4 parts per billion by volume [ppbv]), with seasonal variations, as well as greatly enhanced spikes of CH4 with peak abundances of ∼7 ppbv. What do these CH4 revelations with drastically different abundances and temporal signatures represent in terms of interior geochemical processes, or is martian CH4 a biosignature? Discerning how CH4 generation occurs on Mars may shed light on the potential habitability of Mars. There is no evidence of life on the surface of Mars today, but microbes might reside beneath the surface. In this case, the carbon flux represented by CH4 would serve as a link between a putative subterranean biosphere on Mars and what we can measure above the surface. Alternatively, CH4 records modern geochemical activity. Here we ask the fundamental question: how active is Mars, geochemically and/or biologically? In this article, we examine geological, geochemical, and biogeochemical processes related to our overarching question. The martian atmosphere and surface are an overwhelmingly oxidizing environment, and life requires pairing of electron donors and electron acceptors, that is, redox gradients, as an essential source of energy. Therefore, a fundamental and critical question regarding the possibility of life on Mars is, “Where can we find redox gradients as energy sources for life on Mars?” Hence, regardless of the pathway that generates CH4 on Mars, the presence of CH4, a reduced species in an oxidant-rich environment, suggests the possibility of redox gradients supporting life and habitability on Mars. Recent missions such as ExoMars Trace Gas Orbiter may provide mapping of the global distribution of CH4. To discriminate between abiotic and biotic sources of CH4 on Mars, future studies should use a series of diagnostic geochemical analyses, preferably performed below the ground or at the ground/atmosphere interface, including measurements of CH4 isotopes, methane/ethane ratios, H2 gas concentration, and species such as acetic acid. Advances in the fields of Mars exploration and instrumentation will be driven, augmented, and supported by an improved understanding of atmospheric chemistry and dynamics, deep subsurface biogeochemistry, astrobiology, planetary geology, and geophysics. Future Mars exploration programs will have to expand the integration of complementary areas of expertise to generate synergistic and innovative ideas to realize breakthroughs in advancing our understanding of the potential of life and habitable conditions having existed on Mars. In this spirit, we conducted a set of interdisciplinary workshops. From this series has emerged a vision of technological, theoretical, and methodological innovations to explore the martian subsurface and to enhance spatial tracking of key volatiles, such as CH4.

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Due to the lack of genetically encoded probes for fluorine-19 nuclear magnetic resonance spectroscopy (19F NMR), its utility for probing eukaryotic membrane protein dynamics is limited. Here we report an efficient method for the genetic incorporation of an unnatural amino acid (UAA), 3′-trifluoro­menthyl-phenyl­alanine (mtfF), into cannabinoid receptor 1 (CB1) in the Baculovirus Expression System. The probe can be inserted at any environmentally sensitive site, while causing minimal structural perturbation to the target protein. Using 19F NMR and X-ray crystallography methods, we discovered that the allosteric modulator Org27569 and agonists synergistically stabilize a previously unrecognized pre-active state. An allosteric modulation model is proposed to explain Org27569’s distinct behavior. We demonstrate that our site-specific 19F NMR labeling method is a powerful tool in decoding the mechanism of GPCR allosteric modulation. This new method should be broadly applicable for uncovering conformational states for many important eukaryotic membrane proteins.