Structural features and domain movements controlling substrate binding and cofactor specificity in class II HMG-CoA reductase

The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although inhibition of HMGR by statin drugs is well-understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range of cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data of the enzyme’s cofactor preferences. Our structure of SpHMGR bound with its kinetically preferred NADPH cofactor suggests how NADPH-specific binding and recognition are achieved. In addition, our structure of HMG-CoA-bound SpHMGR reveals large, previously unknown conformational domain movements that may control HMGR substrate binding and enable cofactor exchange without intermediate release during the catalytic cycle. Taken together, this work provides critical new insights into both the HMGR reaction mechanism and the structural basis of cofactor specificity

Structural features and domain movements controlling substrate binding and cofactor specificity in class II HMG-CoA reductase

The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although inhibition of HMGR by statin drugs is well-understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range of cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data of the enzyme’s cofactor preferences. Our structure of SpHMGR bound with its kinetically preferred NADPH cofactor suggests how NADPH-specific binding and recognition are achieved. In addition, our structure of HMG-CoA-bound SpHMGR reveals large, previously unknown conformational domain movements that may control HMGR substrate binding and enable cofactor exchange without intermediate release during the catalytic cycle. Taken together, this work provides critical new insights into both the HMGR reaction mechanism and the structural basis of cofactor specificity

Evidence for High-Frequency QPOs with a 3:2 Frequency Ratio from a 5000 Solar Mass Black Hole

Following the discovery of 3:2 resonance quasi-periodic oscillations (QPOs) in M82X-1 (Pasham et al. 2014), we have constructed power density spectra (PDS) of all 15 (sufficiently long) {\it XMM-Newton} observations of the ultraluminous X-ray source NGC1313X-1 ($L_{X}$ $\approx$ 2$\times$10$^{40}$ erg/sec). We detect a strong QPO at a frequency of 0.29$\pm$0.01 Hz in data obtained on 2012 December 16. Subsequent searching of all the remaining observations for a 3:2/2:3 frequency pair revealed a feature at 0.46$\pm$0.02 Hz on 2003 Dec 13 (frequency ratio of 1.59$\pm$0.09). The global significance of the 0.29 Hz feature considering all frequencies between 0.1 and 4 Hz is $>$ 3.5 $\sigma$. The significance of the 0.46$\pm$0.02 Hz QPO is $>$ 3.5$\sigma$ for a search at 2/3 and 3/2 of 0.29 Hz. We also detect lower frequency QPOs (32.9$\pm$2.6 and 79.7$\pm$1.2 mHz). All the QPOs are super-imposed on a continuum consisting of flat-topped, band-limited noise, breaking into a power-law at a frequency of 16$\pm$3 mHz and white noise at $\gtrsim$ 0.1 Hz. NGC1313X-1's PDS is analogous to stellar-mass black holes' (StMBHs) PDS in the so-called steep power-law state, but with the respective frequencies (both QPOs and break frequencies) scaled down by a factor of $\sim$ 1000. Using the inverse mass-to-high-frequency QPO scaling of StMBHs, we estimate NGC1313X-1's black hole mass to be 5000$\pm$1300 $M_{\odot}$, consistent with an inference from the scaling of the break frequency. However, the implied Eddington ratio, L$_{Edd}$ $>$ 0.03$\pm$0.01, is significantly lower compared to StMBHs in the steep power-law state (L$_{Edd}$ $\gtrsim$ 0.2).Comment: Published in ApJ Letter

On Neutral Absorption and Spectral Evolution in X-ray Binaries

Current X-ray observatories make it possible to follow the evolution of transient and variable X-ray binaries across a broad range in luminosity and source behavior. In such studies, it can be unclear whether evolution in the low energy portion of the spectrum should be attributed to evolution in the source, or instead to evolution in neutral photoelectric absorption. Dispersive spectrometers make it possible to address this problem. We have analyzed a small but diverse set of X-ray binaries observed with the Chandra High Energy Transmission Grating Spectrometer across a range in luminosity and different spectral states. The column density in individual photoelectric absorption edges remains constant with luminosity, both within and across source spectral states. This finding suggests that absorption in the interstellar medium strongly dominates the neutral column density observed in spectra of X-ray binaries. Consequently, evolution in the low energy spectrum of X-ray binaries should properly be attributed to evolution in the source spectrum. We discuss our results in the context of X-ray binary spectroscopy with current and future X-ray missions.Comment: Accepted for publication in ApJ Letter

The Specific Globular Cluster Frequencies of Dwarf Elliptical Galaxies from the Hubble Space Telescope

The specific globular cluster frequencies (S_N) for 24 dwarf elliptical (dE) galaxies in the Virgo and Fornax Clusters and the Leo Group imaged with the Hubble Space Telescope are presented. Combining all available data, we find that for nucleated dEs --- which are spatially distributed like giant ellipticals in galaxy clusters --- S_N(dE,N)=6.5 +- 1.2 and S_N increases with M_V, while for non-nucleated dEs --- which are distributed like late-type galaxies --- S_N(dE,noN)=3.1 +- 0.5 and there is little or no trend with M_V. The S_N values for dE galaxies are thus on average significantly higher than those for late-type galaxies, which have S_N < 1. This suggests that dE galaxies are more akin to giant Es than to late-type galaxies. If there are dormant or stripped irregulars hiding among the dE population, they are likely to be among the non-nucleated dEs. Furthermore, the similarities in the properties of the globular clusters and in the spatial distributions of dE,Ns and giant Es suggest that neither galaxy mass or galaxy metallicity is responsible for high values of S_N. Instead, most metal-poor GCs may have formed in dwarf-sized fragments that merged into larger galaxies.Comment: 12 pages (uses aaspp4.sty), 2 figures, 1 table, to appear in the Astrophysical Journa

Petrov types of slowly rotating fluid balls

Circularly rotating axisymmetric perfect fluid space-times are investigated to second order in the small angular velocity. The conditions of various special Petrov types are solved in a comoving tetrad formalism. A number of theorems are stated on the possible Petrov types of various fluid models. It is shown that Petrov type II solutions must reduce to the de Sitter spacetime in the static limit. Two space-times with a physically satisfactory energy-momentum tensor are investigated in detail. For the rotating incompressible fluid, it is proven that the Petrov type cannot be D. The equation of the rotation function $\omega$ can be solved for the Tolman type IV fluid in terms of quadratures. It is also shown that the rotating version of the Tolman IV space-time cannot be Petrov type D.Comment: 14 pages, version to appear in Gen. Rel. Gra

Magnetic field dependence of the internal quality factor and noise performance of lumped-element kinetic inductance detectors

We present a technique for increasing the internal quality factor of kinetic inductance detectors (KIDs) by nulling ambient magnetic fields with a properly applied magnetic field. The KIDs used in this study are made from thin-film aluminum, they are mounted inside a light-tight package made from bulk aluminum, and they are operated near $150 \, \mathrm{mK}$. Since the thin-film aluminum has a slightly elevated critical temperature ($T_\mathrm{c} = 1.4 \, \mathrm{K}$), it therefore transitions before the package ($T_\mathrm{c} = 1.2 \, \mathrm{K}$), which also serves as a magnetic shield. On cooldown, ambient magnetic fields as small as approximately $30 \, \mathrm{\mu T}$ can produce vortices in the thin-film aluminum as it transitions because the bulk aluminum package has not yet transitioned and therefore is not yet shielding. These vortices become trapped inside the aluminum package below $1.2 \, \mathrm{K}$ and ultimately produce low internal quality factors in the thin-film superconducting resonators. We show that by controlling the strength of the magnetic field present when the thin film transitions, we can control the internal quality factor of the resonators. We also compare the noise performance with and without vortices present, and find no evidence for excess noise beyond the increase in amplifier noise, which is expected with increasing loss.Comment: 5 pages, 4 figure