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At least 775 records · Page 43

Secondary PDZ domain-binding site on class B plexins enhances the affinity for PDZ–RhoGEF

PDZ domains are abundant protein interaction modules and typically recognize a short motif at the C terminus of their ligands, with a few residues in the motif endowing the binding specificity. The sequence-based rules, however, cannot fully account for the specificity between the vast number of PDZ domains and ligands in the cell. Plexins are transmembrane receptors that regulate processes such as axon guidance and angiogenesis. Two related guanine nucleotide exchange factors (GEFs), PDZ–RhoGEF and leukemia-associated RhoGEF (LARG), use their PDZ domains to bind class B plexins and play critical roles in signaling. Here, we present the crystal structure of the full-length cytoplasmic region of PlexinB2 in complex with the PDZ domain of PDZ–RhoGEF. The structure reveals that, in addition to the canonical C-terminal motif/PDZ interaction, the 3D domain of PlexinB2 forms a secondary interface with the PDZ domain. Our biophysical and cell-based assays show that the secondary interface contributes to the specific interaction between plexin and PDZ–RhoGEF and to signaling by plexin in the cell. As a result, formation of secondary interfaces may be a general mechanism for increasing affinity and specificity of modular domain-mediated interactions.

59 BASIC BIOLOGICAL SCIENCES↗

Crystal structure of Pistol, a class of self-cleaving ribozyme

Small self-cleaving ribozymes have been discovered in all evolutionary domains of life. They can catalyze site-specific RNA cleavage, and as a result, they have relevance in gene regulation. Comparative genomic analysis has led to the discovery of a new class of small self-cleaving ribozymes named Pistol. We report herein the crystal structure of Pistol at 2.97-Å resolution. Our results suggest that the Pistol ribozyme self-cleavage mechanism likely uses a guanine base in the active site pocket to carry out the phosphoester transfer reaction. The guanine G40 is in close proximity to serve as the general base for activating the nucleophile by deprotonating the 2'-hydroxyl to initiate the reaction (phosphoester transfer). Furthermore, G40 can also establish hydrogen bonding interactions with the nonbridging oxygen of the scissile phosphate. The proximity of G32 to the O5' leaving group suggests that G32 may putatively serve as the general acid. The RNA structure of Pistol also contains A-minor interactions, which seem to be important to maintain its tertiary structure and compact fold. Our findings expand the repertoire of ribozyme structures and highlight the conserved evolutionary mechanism used by ribozymes for catalysis.

59 BASIC BIOLOGICAL SCIENCES↗

Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab

The rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen–antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 Å resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

60 APPLIED LIFE SCIENCES↗

Architecture of Pseudomonas aeruginosa glutamyl-tRNA synthetase defines a subfamily of dimeric class Ib aminoacyl-tRNA synthetases

The aminoacyl-tRNA synthetases (AaRSs) are an ancient family of structurally diverse enzymes that are divided into two major classes. The functionalities of most AaRSs are inextricably linked to their oligomeric states. While GluRSs were previously classified as monomers, the current investigation reveals that the form expressed in Pseudomonas aeruginosa is a rotationally pseudosymmetrical homodimer featuring intersubunit tRNA binding sites. Both subunits display a highly bent, "pipe strap" conformation, with the anticodon binding domain directed toward the active site. The tRNA binding sites are similar in shape to those of the monomeric GluRSs, but are formed through an approximately 180-degree rotation of the anticodon binding domains and dimerization via the anticodon and D-arm binding domains. As a result, each anticodon binding domain is poised to recognize the anticodon loop of a tRNA bound to the adjacent protomer. Additionally, the anticodon binding domain has an α-helical C-terminal extension containing a conserved lysine-rich consensus motif positioned near the predicted location of the acceptor arm, suggesting dual functions in tRNA recognition. The unique architecture of PaGluRS broadens the structural diversity of the GluRS family, and member synthetases of all bacterial AaRS subclasses have now been identified that exhibit oligomerization.

Fenwick, Michael K↗

A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2-C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30-50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2-C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H+-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2-C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.

3CLpro inhibitor↗

ORIGIN OF THE 'He/N' AND 'Fe II' SPECTRAL CLASSES OF NOVAE

The spectra of postoutburst novae display either He+N or Fe II lines as the most prominent non-Balmer lines at maximum light. Spectral diagnostics indicate physical conditions for 'He/N' spectra that are consistent with their origin in the white dwarf (WD) ejecta, whereas 'Fe II' spectra point to their formation in a large circumbinary envelope of gas whose origin is the secondary star. A determining parameter for which of the two types of spectra predominate may be the binary mass ratio M{sub sec}/M{sub WD}. The increasing fraction of novae that are observed to be 'hybrid' objects, where both classes of spectra appear sequentially, is explained by changing parameters in the two emitting regions during the postoutburst decline. We argue that most novae may be hybrids that show both types of spectra during decline. The emission line intensity ratio O I {lambda}8446/{lambda}7773 is suggested as a good density diagnostic for the ejecta, and a finding list of emission lines identified in recent spectroscopic surveys of novae is presented as an aid to future line identification work.

79 ASTRONOMY AND ASTROPHYSICS↗

COMPARISON OF TWO EPOCHS OF THE ZEEMAN EFFECT IN THE 44 GHz CLASS I METHANOL (CH{sub 3}OH) MASER LINE IN OMC-2

We present a second epoch of observations of the 44 GHz Class I methanol maser line toward the star-forming region Orion Molecular Cloud 2. The observations were carried out with the Very Large Array, and constitute one of the first successful Zeeman effect detections with the new Wide-band Digital Architecture correlator. Comparing to the result of our earlier epoch of data for this region, we find that the intensity of the maser increased by 50%, but the magnetic field value has stayed the same, within the errors. This suggests that the methanol maser may be tracing the large-scale magnetic field that is not affected by the bulk gas motions or turbulence on smaller scales that is causing the change in maser intensity.

79 ASTRONOMY AND ASTROPHYSICS↗

DISCOVERY OF A NEW PHOTOMETRIC SUB-CLASS OF FAINT AND FAST CLASSICAL NOVAE

We present photometric and spectroscopic follow-up of a sample of extragalactic novae discovered by the Palomar 60 inch telescope during a search for 'Fast Transients In Nearest Galaxies' (P60-FasTING). Designed as a fast cadence (1 day) and deep (g < 21 mag) survey, P60-FasTING was particularly sensitive to short-lived and faint optical transients. The P60-FasTING nova sample includes 10 novae in M 31, 6 in M 81, 3 in M 82, 1 in NGC 2403, and 1 in NGC 891. This significantly expands the known sample of extragalactic novae beyond the Local Group, including the first discoveries in a starburst environment. Surprisingly, our photometry shows that this sample is quite inconsistent with the canonical maximum-magnitude-rate-of-decline (MMRD) relation for classical novae. Furthermore, the spectra of the P60-FasTING sample are indistinguishable from classical novae. We suggest that we have uncovered a sub-class of faint and fast classical novae in a new phase space in luminosity-timescale of optical transients. Thus, novae span two orders of magnitude in both luminosity and time. Perhaps the MMRD, which is characterized only by the white dwarf mass, was an oversimplification. Nova physics appears to be characterized by a relatively rich four-dimensional parameter space in white dwarf mass, temperature, composition, and accretion rate.

79 ASTRONOMY AND ASTROPHYSICS↗

ANATOMY OF A SOLAR FLARE: MEASUREMENTS OF THE 2006 DECEMBER 14 X-CLASS FLARE WITH GONG, HINODE, AND RHESSI

Some of the most challenging observations to explain in the context of existing flare models are those related to the lower atmosphere and below the solar surface. Such observations, including changes in the photospheric magnetic field and seismic emission, indicate the poorly understood connections between energy release in the corona and its impact in the photosphere and the solar interior. Using data from Hinode, TRACE, RHESSI, and GONG we study the temporal and spatial evolution of the 2006 December 14 X-class flare in the chromosphere, photosphere, and the solar interior. We investigate the connections between the emission at various atmospheric depths, including acoustic signatures obtained by time-distance and holography methods from the GONG data. We report the horizontal displacements observed in the photosphere linked to the timing and locations of the acoustic signatures we believe to be associated with this flare, their vertical and horizontal displacement velocities, and their potential implications for current models of flare dynamics.

79 ASTRONOMY AND ASTROPHYSICS↗

COMPLEX STRUCTURE IN CLASS 0 PROTOSTELLAR ENVELOPES. II. KINEMATIC STRUCTURE FROM SINGLE-DISH AND INTERFEROMETRIC MOLECULAR LINE MAPPING

We present a study of dense molecular gas kinematics in 17 nearby protostellar systems using single-dish and interferometric molecular line observations. The non-axisymmetric envelopes around a sample of Class 0/I protostars were mapped in the N{sub 2}H{sup +} (J = 1 {yields} 0) tracer with the IRAM 30 m, CARMA, and Plateau de Bure Interferometer, as well as NH{sub 3} (1,1) with the Very Large Array. The molecular line emission is used to construct line-center velocity and linewidth maps for all sources to examine the kinematic structure in the envelopes on spatial scales from 0.1 pc to {approx}1000 AU. The direction of the large-scale velocity gradients from single-dish mapping is within 45{sup 0} of normal to the outflow axis in more than half the sample. Furthermore, the velocity gradients are often quite substantial, the average being {approx}2.3 km s{sup -1} pc{sup -1}. The interferometric data often reveal small-scale velocity structure, departing from the more gradual large-scale velocity gradients. In some cases, this likely indicates accelerating infall and/or rotational spin-up in the inner envelope; the median velocity gradient from the interferometric data is {approx}10.7 km s{sup -1} pc{sup -1}. In two systems, we detect high-velocity HCO{sup +} (J = 1 {yields} 0) emission inside the highest-velocity N{sub 2}H{sup +} emission. This enables us to study the infall and rotation close to the disk and estimate the central object masses. The velocity fields observed on large and small scales are more complex than would be expected from rotation alone, suggesting that complex envelope structure enables other dynamical processes (i.e., infall) to affect the velocity field.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

IMPULSIVE PHASE CORONAL HARD X-RAY SOURCES IN AN X3.9 CLASS SOLAR FLARE

We present the analysis of a pair of unusually energetic coronal hard X-ray (HXR) sources detected by the Reuven Ramaty High Energy Solar Spectroscopic Imager during the impulsive phase of an X3.9 class solar flare on 2003 November 3, which simultaneously shows two intense footpoint (FP) sources. A distinct loop top (LT) coronal source is detected up to {approx}150 keV and a second (upper) coronal source up to {approx}80 keV. These photon energies, which were not fully investigated in earlier analysis of this flare, are much higher than commonly observed in coronal sources and pose grave modeling challenges. The LT source in general appears higher in altitude with increasing energy and exhibits a more limited motion compared to the expansion of the thermal loop. The high-energy LT source shows an impulsive time profile and its nonthermal power-law spectrum exhibits soft-hard-soft evolution during the impulsive phase, similar to the FP sources. The upper coronal source exhibits an opposite spatial gradient and a similar spectral slope compared to the LT source. These properties are consistent with the model of stochastic acceleration of electrons by plasma waves or turbulence. However, the LT and FP spectral index difference (varying from {approx}0 to 1) is much smaller than commonly measured and than that expected from a simple stochastic acceleration model. Additional confinement or trapping mechanisms of high-energy electrons in the corona are required. Comprehensive modeling including both kinetic effects and the macroscopic flare structure may shed light on this behavior. These results highlight the importance of imaging spectroscopic observations of the LT and FP sources up to high energies in understanding electron acceleration in solar flares. Finally, we show that the electrons producing the upper coronal HXR source may very likely be responsible for the type III radio bursts at the decimetric/metric wavelength observed during the impulsive phase of this flare.

79 ASTRONOMY AND ASTROPHYSICS↗

SPECTROPOLARIMETRY OF C-CLASS FLARE FOOTPOINTS

We investigate the decay phase of a C-class flare in full-Stokes imaging spectropolarimetry with quasi-simultaneous measurements in the photosphere (6302.5 A line) and in the chromosphere (8542 A line) with the IBIS instrument. We analyze data from two fields of view, each spanning about 40'' Multiplication-Sign 80'' and targeting the two footpoints of the flare. A region of interest is identified from V/I images: a patch of opposite polarity in the smaller sunspot's penumbra. We find unusual flows in this patch at photospheric levels: a Doppler shift of -4 km s{sup -1}, but also a possible radial inflow into the sunspot of 4 km s{sup -1}. Such patches seem to be common during flares, but only high-resolution observations allowed us to see the inflow, which may be related to future flares observed in this region. Chromospheric images show variable overlying emission and flows and unusual Stokes profiles. We also investigate the irregular penumbra, whose formation may be blocked by the opposite polarity patch and flux emergence. The 40 minute temporal evolution depicts the larger of the flare ribbons becoming fainter and changing its shape. Measurable photospheric magnetic fields remain constant and we do not detect flare energy transport down from the chromosphere. We find no clear indications of impact polarization in the 8542 A line. We cannot exclude the possibility of impact polarization, because weaker signals may be buried in the prominent Zeeman signatures or it may have been present earlier during the flare.

79 ASTRONOMY AND ASTROPHYSICS↗

THE HUBBLE WIDE FIELD CAMERA 3 TEST OF SURFACES IN THE OUTER SOLAR SYSTEM: THE COMPOSITIONAL CLASSES OF THE KUIPER BELT

We present the first results of the Hubble Wide Field Camera 3 Test of Surfaces in the Outer Solar System. The purpose of this survey was to measure the surface properties of a large number of Kuiper Belt objects and attempt to infer compositional and dynamical correlations. We find that the Centaurs and the low-perihelion scattered disk and resonant objects exhibit virtually identical bifurcated optical color distributions and make up two well-defined groups of objects. Both groups have highly correlated optical and NIR colors that are well described by a pair of two-component mixture models that have different red components but share a common neutral component. The small, H{sub 606} {approx}> 5.6 high-perihelion excited objects are entirely consistent with being drawn from the two branches of the mixing model, suggesting that the color bifurcation of the Centaurs is apparent in all small excited objects. On the other hand, objects larger than H{sub 606} {approx} 5.6 are not consistent with the mixing model, suggesting some evolutionary process avoided by the smaller objects. The existence of a bifurcation amongst all excited populations argues that the two separate classes of object existed in the primordial disk before the excited Kuiper Belt was populated. The cold classical objects exhibit a different type of surface that has colors that are consistent with being drawn from the red branch of the mixing model, but with much higher albedos.

79 ASTRONOMY AND ASTROPHYSICS↗

THE ENVELOPE AND EMBEDDED DISK AROUND THE CLASS 0 PROTOSTAR L1157-mm: DUAL-WAVELENGTH INTERFEROMETRIC OBSERVATIONS AND MODELING

We present dual-wavelength observations and modeling of the nearly edge-on Class 0 young stellar object L1157-mm. Using the Combined Array for Research in Millimeter-wave Astronomy, a nearly spherical structure is seen from the circumstellar envelope at the size scale of 10{sup 2}-10{sup 3} AU in both 1 mm and 3 mm dust emission. Radiative transfer modeling is performed to compare data with theoretical envelope models, including a power-law envelope model and the Terebey-Shu-Cassen model. Bayesian inference is applied for parameter estimation and information criterion is used for model selection. The results prefer the power-law envelope model against the Terebey-Shu-Cassen model. In particular, for the power-law envelope model, a steep density profile with an index of {approx}2 is inferred. Moreover, the dust opacity spectral index {beta} is estimated to be {approx}0.9, implying that grain growth has started at L1157-mm. Also, the unresolved disk component is constrained to be {approx}<40 AU in radius and {approx}<4-25 M{sub Jup} in mass. However, the estimate of the embedded disk component relies on the assumed envelope model.

79 ASTRONOMY AND ASTROPHYSICS↗

NEW CLASS OF VERY HIGH ENERGY {gamma}-RAY EMITTERS: RADIO-DARK MINI SHELLS SURROUNDING ACTIVE GALACTIC NUCLEUS JETS

We explore non-thermal emission from a shocked interstellar medium, which is identified as an expanding shell, driven by a relativistic jet in active galactic nuclei (AGNs). In this work, we particularly focus on parsec-scale size mini shells surrounding mini radio lobes. From the radio to X-ray band, the mini radio lobe emission dominates the faint emission from the mini shell. On the other hand, we find that inverse-Compton (IC) emission from the shell can overwhelm the associated lobe emission at the very high energy (VHE; E > 100 GeV) {gamma}-ray range, because energy densities of synchrotron photons from the lobe and/or soft photons from the AGN nucleus are large and IC scattering works effectively. The predicted IC emission from nearby mini shells can be detected with the Cherenkov Telescope Array and they are potentially a new class of VHE {gamma}-ray emitters.

79 ASTRONOMY AND ASTROPHYSICS↗

HOT WATER IN THE INNER 100 AU OF THE CLASS 0 PROTOSTAR NGC 1333 IRAS2A

Evaporation of water ice above 100 K in the inner few 100 AU of low-mass embedded protostars (the so-called hot core) should produce quiescent water vapor abundances of {approx}10{sup -4} relative to H{sub 2}. Observational evidence so far points at abundances of only a few 10{sup -6}. However, these values are based on spherical models, which are known from interferometric studies to be inaccurate on the relevant spatial scales. Are hot cores really that much drier than expected, or are the low abundances an artifact of the inaccurate physical models? We present deep velocity-resolved Herschel-HIFI spectra of the 3{sub 12}-3{sub 03} lines of H{sub 2}{sup 16}O and H{sub 2}{sup 18}O (1097 GHz, E{sub u}/k = 249 K) in the low-mass Class 0 protostar NGC 1333 IRAS2A. A spherical radiative transfer model with a power-law density profile is unable to reproduce both the HIFI data and existing interferometric data on the H{sub 2}{sup 18}O 3{sub 13}-2{sub 20} line (203 GHz, E{sub u}/k = 204 K). Instead, the HIFI spectra likely show optically thick emission from a hot core with a radius of about 100 AU. The mass of the hot core is estimated from the C{sup 18}O J = 9-8 and 10-9 lines. We derive a lower limit to the hot water abundance of 2 Multiplication-Sign 10{sup -5}, consistent with the theoretical predictions of {approx}10{sup -4}. The revised HDO/H{sub 2}O abundance ratio is 1 Multiplication-Sign 10{sup -3}, an order of magnitude lower than previously estimated.

79 ASTRONOMY AND ASTROPHYSICS↗

THE ROTATING OUTFLOW, ENVELOPE, AND DISK OF THE CLASS-0/I PROTOSTAR [BHB2007] no. 11 IN THE PIPE NEBULA

We present the results of observations toward a low-mass Class-0/I protostar [BHB2007] no. 11 (B59 no. 11) in the nearby (d = 130 pc) star-forming region Barnard 59 (B59), in the Pipe Nebula. We utilize the Atacama Submillimeter Telescope Experiment (ASTE) 10 m telescope ({approx}22'' resolution), focusing on the CO(3-2), HCO{sup +}, H{sup 13}CO{sup +}(4-3), and 1.1 mm dust-continuum emission transitions. We also show Submillimeter Array (SMA) data with {approx}5'' resolution in {sup 12}CO, {sup 13}CO, C{sup 18}O(2-1), and 1.3 mm dust-continuum emission. From ASTE CO(3-2) observations, we found that B59 no. 11 is blowing a collimated outflow whose axis lies almost on the plane of the sky. The outflow traces well a cavity-like structure seen in the 1.1 mm dust-continuum emission. The results of SMA {sup 13}CO and C{sup 18}O(2-1) observations have revealed that a compact and elongated structure of dense gas is associated with B59 no. 11; the structure is oriented perpendicular to the outflow axis. There is a compact dust condensation with a size of 350 Multiplication-Sign 180 AU seen in the SMA 1.3 mm continuum map, and the direction of its major axis is almost the same as that of the dense gas elongation. The distributions of {sup 13}CO and C{sup 18}O emission also show velocity gradients along their major axes, which are thought to arise from the envelope/disk rotation. From detailed analysis of the SMA data, we infer that B59 no. 11 is surrounded by a Keplerian disk with a radius of less than 350 AU. In addition, the SMA CO(2-1) image shows a velocity gradient in the outflow in the same direction as that of the dense gas rotation. We suggest that this velocity gradient indicates rotation in the outflow.

79 ASTRONOMY AND ASTROPHYSICS↗

EMISSION HEIGHT AND TEMPERATURE DISTRIBUTION OF WHITE-LIGHT EMISSION OBSERVED BY HINODE/SOT FROM THE 2012 JANUARY 27 X-CLASS SOLAR FLARE

White-light emissions were observed from an X1.7 class solar flare on 2012 January 27, using three continuum bands (red, green, and blue) of the Solar Optical Telescope on board the Hinode satellite. This event occurred near the solar limb, and so differences in the locations of the various emissions are consistent with differences in heights above the photosphere of the various emission sources. Under this interpretation, our observations are consistent with the white-light emissions occurring at the lowest levels of where the Ca II H emission occurs. Moreover, the centers of the source regions of the red, green, and blue wavelengths of the white-light emissions are significantly displaced from each other, suggesting that those respective emissions are emanating from progressively lower heights in the solar atmosphere. The temperature distribution was also calculated from the white-light data, and we found the lower-layer emission to have a higher temperature. This indicates that high-energy particles penetrated down to near the photosphere, and deposited heat into the ambient lower layers of the atmosphere.

79 ASTRONOMY AND ASTROPHYSICS↗