Molecular dynamics simulations of apo and holo forms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules

Structural and dynamic properties from a series of 300 ns molecular dynamics, MD, simulations of two intracellular lipid binding proteins, iLBPs, (Fatty Acid Binding Protein 5, FABP5, and Cellular Retinoic Acid Binding Protein II, CRABP-II) in both the apo form and when bound with retinoic acid reveal a high degree of protein and ligand flexibility. The ratio of FABP5 to CRABP-II in a cell may determine whether it undergoes natural apoptosis or unrestricted cell growth in the presence of retinoic acid. As a result, FABP5 is a promising target for cancer therapy. The MD simulations presented here reveal distinct differences in the two proteins and provide insight into the bindingmechanism. CRABP-II is a much larger, more flexible protein that closes upon ligand binding, where FABP5 transitions to an open state in the holo form. The traditional understanding obtained from crystal structures of the gap between two β-sheets of the β-barrel common to iLBPs and the α-helix cap that forms the portal to the binding pocket is insufficient for describing protein conformation (open vs. closed) or ligand entry and exit. When the high degree of mobility between multiple conformations of both the ligand and protein are examined via MD simulation, a new mode of ligand motion that improves understanding of binding dynamics is revealed

Molecular dynamics simulations of <i>apo</i> and <i>holo</i> forms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules

<p>Structural and dynamic properties from a series of 300 ns molecular dynamics, MD, simulations of two intracellular lipid binding proteins, iLBPs, (Fatty Acid Binding Protein 5, FABP5, and Cellular Retinoic Acid Binding Protein II, CRABP-II) in both the apo form and when bound with retinoic acid reveal a high degree of protein and ligand flexibility. The ratio of FABP5 to CRABP-II in a cell may determine whether it undergoes natural apoptosis or unrestricted cell growth in the presence of retinoic acid. As a result, FABP5 is a promising target for cancer therapy. The MD simulations presented here reveal distinct differences in the two proteins and provide insight into the binding mechanism. CRABP-II is a much larger, more flexible protein that closes upon ligand binding, where FABP5 transitions to an open state in the holo form. The traditional understanding obtained from crystal structures of the gap between two β-sheets of the β-barrel common to iLBPs and the α-helix cap that forms the portal to the binding pocket is insufficient for describing protein conformation (open vs. closed) or ligand entry and exit. When the high degree of mobility between multiple conformations of both the ligand and protein are examined via MD simulation, a new mode of ligand motion that improves understanding of binding dynamics is revealed.</p

One Bridge, Three Bonds: A Frontier in Multiple Bonding in Heterobimetallic Complexes

A single bridging phosphinoamide ligand was shown to support a metal–metal triple bond in a Zr/Co heterobimetallic complex. The similarity of the bonding in this compound to previously synthesized Zr/Co species, and therefore the assignment of the Zr/Co triple bond, is supported by the structural parameters of the complex, the electronic structure predicted by density functional theory, and complete-active-space self-consistent-field (CASSCF) calculations. This demonstrates that metal–metal multiple bonds can be realized in heterobimetallic complexes without multiple bridging ligands to enforce the proximity of the two metals

Tracking Lithium Ions via Widefield Fluorescence Microscopy for Battery Diagnostics

Direct tracking of lithium ions with time and spatial resolution can provide an important diagnostic tool for understanding mechanisms in lithium ion batteries. A fluorescent indicator of lithium ions, 2-(2-hydroxyphenyl)­naphthoxazole, was synthesized and used for real-time tracking of lithium ions via widefield fluorescence microscopy. The fluorophore can be excited with visible light and was shown to enable quantitative determination of the lithium ion diffusion constant in a microfluidic model system for a plasticized polymer electrolyte lithium battery. The use of widefield fluorescence microscopy for in situ tracking of lithium ions in batteries is discussed

Activation of tyrosine kinases by mutation of the gatekeeper threonine

threonin

Discovery of type II inhibitors of tgfβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)

We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1<i>H</i>-pyrrolo­[2,3-<i>b</i>]­pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as <b>1</b> (NG25) and <b>2</b> as well as MAP4K2 selective inhibitors such as <b>16</b> and <b>17</b>. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with <b>1</b> confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors

Observation of New Ξc0\Xi_c^0 Baryons Decaying to Λc+K−\Lambda_c^+ K^-

International audienceThe Λc+K- mass spectrum is studied with a data sample of pp collisions at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 5.6  fb-1 collected by the LHCb experiment. Three Ξc0 states are observed with a large significance and their masses and natural widths are measured to be m[Ξc(2923)0]=2923.04±0.25±0.20±0.14  MeV, Γ[Ξc(2923)0]=7.1±0.8±1.8  MeV, m[Ξc(2939)0]=2938.55±0.21±0.17±0.14  MeV, Γ[Ξc(2939)0]=10.2±0.8±1.1  MeV, m[Ξc(2965)0]=2964.88±0.26±0.14±0.14  MeV, Γ[Ξc(2965)0]=14.1±0.9±1.3  MeV, where the uncertainties are statistical, systematic, and due to the limited knowledge of the Λc+ mass. The Ξc(2923)0 and Ξc(2939)0 baryons are new states. The Ξc(2965)0 state is in the vicinity of the known Ξc(2970)0 baryon; however, their masses and natural widths differ significantly

Search for the Rare Decays Bs0→e+e−B^0_s\to e^+e^- and B0→e+e−B^0\to e^+e^-

International audienceA search for the decays Bs0→e+e- and B0→e+e- is performed using data collected with the LHCb experiment in proton-proton collisions at center-of-mass energies of 7, 8, and 13 TeV, corresponding to integrated luminosities of 1, 2, and 2  fb-1, respectively. No signal is observed. Assuming no contribution from B0→e+e- decays, an upper limit on the branching fraction B(Bs0→e+e-)<9.4(11.2)×10-9 is obtained at 90(95)% confidence level. If no Bs0→e+e- contribution is assumed, a limit of B(B0→e+e-)<2.5(3.0)×10-9 is determined at 90(95)% confidence level. These upper limits are more than one order of magnitude lower than the previous values

Precision measurement of the Bc+B_{c}^{+} meson mass

International audienceA precision measurement of the ${B}_c^{+}$ meson mass is performed using proton- proton collision data collected with the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to a total integrated luminosity of 9.0 fb$^{−1}$. The ${B}_c^{+}$ mesons are reconstructed via the decays ${B}_c^{+}$→ J/ψπ$^{+}$, ${B}_c^{+}$→ J/ψπ$^{+}$π$^{−}$π$^{+}$, ${B}_c^{+}\to J/\psi p\overline{p}{\pi}^{+}$, ${B}_c^{+}\to J/\psi {D}_s^{+}$, ${B}_c^{+}$→ J/ψ D$^{0}$K$^{+}$ and ${B}_c^{+}\to {B}_s^0{\pi}^{+}$. Combining the results of the individual decay channels, the ${B}_c^{+}$ mass is measured to be 6274.47 ± 0.27 (stat) ± 0.17 (syst) MeV/c$^{2}$. This is the most precise measurement of the ${B}_c^{+}$ mass to date. The difference between the ${B}_c^{+}$ and ${B}_s^0$ meson masses is measured to be 907.75 ± 0.37 (stat) ± 0.27 (syst) MeV/c.[graphic not available: see fulltext