Structural Dynamics-Us最新文献

{"title":"Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT","authors":"A. Gardberg, Annissa J Huhn, R. Cummings, A. Bommi-Reddy, F. Poy, J. Setser, V. Vivat, F. Brucelle, Jonathan E. Wilson","doi":"10.1063/1.5119336","DOIUrl":"https://doi.org/10.1063/1.5119336","url":null,"abstract":"Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5119336","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45748858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of a bound anion on the structure and dynamics of halorhodopsin from Natronomonas pharaonis","authors":"M. Mizuno, Yumi Shimoo, H. Kandori, Y. Mizutani","doi":"10.1063/1.5125621","DOIUrl":"https://doi.org/10.1063/1.5125621","url":null,"abstract":"Active ion transport across membranes is vital to maintaining the electrochemical gradients of ions in cells and is mediated by transmembrane proteins. Halorhodopsin (HR) functions as a light-driven inward pump for chloride ions. The protein contains all-trans-retinal bound to a specific lysine residue through a protonated Schiff base. Interaction between the bound chloride ion and the protonated Schiff base is crucial for ion transport because chloride ion movement is driven by the flipping of the protonated Schiff base upon photoisomerization. However, it remains unknown how this interaction evolves in the HR photocycle. Here, we addressed the effect of the bound anion on the structure and dynamics of HR from Natronomonas pharaonis in the early stage of the photocycle. Comparison of the chloride-bound, formate-bound, and anion-depleted forms provided insights into the interaction between the bound anion and the chromophore/protein moiety. In the unphotolyzed state, the bound anion affects the π-conjugation of the polyene chain and the hydrogen bond of the protonated Schiff base of the retinal chromophore. Picosecond time scale measurements showed that the band intensities of the W16 and W18 modes of the tryptophan residues decreased instantaneously upon photoexcitation of the formate-bound form. In contrast, these intensity decreases were delayed for the chloride-bound and anion-depleted forms. These observations suggest the stronger interactions of the bound formate ion with the retinal chromophore and the chromophore pocket. On the nanosecond to microsecond timescales, we found that the interaction between the protonated Schiff base and the bound ion is broken upon formation of the K intermediate and is recovered following translocation of the bound anion toward the protonated Schiff base in the L intermediate. Our results demonstrate that the hydrogen-bonding ability of the bound anion plays an essential role in the ion transport of light-driven anion pumps.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5125621","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47358070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A versatile experimental system for tracking ultrafast chemical reactions with X-ray free-electron lasers","authors":"T. Katayama, S. Nozawa, Y. Umena, Sung-Hak Lee, T. Togashi, S. Owada, M. Yabashi","doi":"10.1063/1.5111795","DOIUrl":"https://doi.org/10.1063/1.5111795","url":null,"abstract":"An experimental system, SPINETT (SACLA Pump-probe INstrumEnt for Tracking Transient dynamics), dedicated for ultrafast pump-probe experiments using X-ray free-electron lasers has been developed. SPINETT consists of a chamber operated under 1 atm helium pressure, two Von Hamos spectrometers, and a large two-dimensional detector having a short work distance. This platform covers complementary X-ray techniques; one can perform time-resolved X-ray absorption spectroscopy, time-resolved X-ray emission spectroscopy, and time-resolved X-ray diffuse scattering. Two types of liquid injectors have been prepared for low-viscosity chemical solutions and for protein microcrystals embedded in a matrix. We performed a test experiment at SPring-8 Angstrom Compact free-electron LAser and demonstrated the capability of SPINETT to obtain the local electronic structure and geometrical information simultaneously.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5111795","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44252937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights and innovation from a million crystal structures in the Cambridge Structural Database.","authors":"Jason C Cole,&nbsp;Seth Wiggin,&nbsp;Francesca Stanzione","doi":"10.1063/1.5116878","DOIUrl":"https://doi.org/10.1063/1.5116878","url":null,"abstract":"<p><p>The Cambridge Structural Database (CSD) is the world's largest and most comprehensive collection of organic, organometallic, and metal-organic crystal structure information. Analyses using the data have wide impact across the chemical sciences in allowing understanding of structural preferences. In this short review, we illustrate the more common methods by which CSD data influence molecular design. We show how more data could lead to more refined insights into the future using a simple example of trifluoromethylphenyl fragments, highlighting how with sufficient data one can build a reasonable model of geometric change in a chemical fragment with torsional rotation, and show some recent examples where the CSD has been used in conjunction with other methods to provide design ideas and more computationally tractable workflows for derivation of useful insights into structural design.</p>","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":"6 5","pages":"054301"},"PeriodicalIF":2.8,"publicationDate":"2019-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5116878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure determination of the tetracene dimer in helium nanodroplets using femtosecond strong-field ionization.","authors":"Constant Schouder,&nbsp;Adam S Chatterley,&nbsp;Florent Calvo,&nbsp;Lars Christiansen,&nbsp;Henrik Stapelfeldt","doi":"10.1063/1.5118005","DOIUrl":"https://doi.org/10.1063/1.5118005","url":null,"abstract":"<p><p>Dimers of tetracene molecules are formed inside helium nanodroplets and identified through covariance analysis of the emission directions of kinetic tetracene cations stemming from femtosecond laser-induced Coulomb explosion. Next, the dimers are aligned in either one or three dimensions under field-free conditions by a nonresonant, moderately intense laser pulse. The experimental angular covariance maps of the tetracene ions are compared to calculated covariance maps for seven different dimer conformations and found to be consistent with four of these. Additional measurements of the alignment-dependent strong-field ionization yield of the dimer narrow the possible conformations down to either a slipped-parallel or parallel-slightly rotated structure. According to our quantum chemistry calculations, these are the two most stable gas-phase conformations of the dimer and one of them is favorable for singlet fission.</p>","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":"6 4","pages":"044301"},"PeriodicalIF":2.8,"publicationDate":"2019-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5118005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the multiparameter nature of EUV-visible wave mixing at the FERMI FEL.","authors":"L Foglia,&nbsp;F Capotondi,&nbsp;H Höppner,&nbsp;A Gessini,&nbsp;L Giannessi,&nbsp;G Kurdi,&nbsp;I Lopez Quintas,&nbsp;C Masciovecchio,&nbsp;M Kiskinova,&nbsp;R Mincigrucci,&nbsp;D Naumenko,&nbsp;I P Nikolov,&nbsp;E Pedersoli,&nbsp;G M Rossi,&nbsp;A Simoncig,&nbsp;F Bencivenga","doi":"10.1063/1.5111501","DOIUrl":"https://doi.org/10.1063/1.5111501","url":null,"abstract":"<p><p>The rapid development of extreme ultraviolet (EUV) and x-ray ultrafast coherent light sources such as free electron lasers (FELs) has triggered the extension of wave-mixing techniques to short wavelengths. This class of experiments, based on the interaction of matter with multiple light pulses through the <i>N</i>th order susceptibility, holds the promise of combining intrinsic ultrafast time resolution and background-free signal detection with nanometer spatial resolution and chemical specificity. A successful approach in this direction has been the combination of the unique characteristics of the seeded FEL FERMI with dedicated four-wave-mixing (FWM) setups, which leads to the demonstration of EUV-based transient grating (TG) spectroscopy. In this perspective paper, we discuss how the TG approach can be extended toward more general FWM spectroscopies by exploring the intrinsic multiparameter nature of nonlinear processes, which derives from the ability of controlling the properties of each field independently.</p>","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":"6 4","pages":"040901"},"PeriodicalIF":2.8,"publicationDate":"2019-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5111501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FACT and FAIR with Big Data allows objectivity in science: The view of crystallography","authors":"J. Helliwell","doi":"10.1063/1.5124439","DOIUrl":"https://doi.org/10.1063/1.5124439","url":null,"abstract":"A publication is an important narrative of the work done and interpretations made by researchers securing a scientific discovery. As The Royal Society neatly states though, “Nullius in verba” (“Take nobody's word for it”), whereby the role of the underpinning data is paramount. Therefore, the objectivity that preserving that data within the article provides is due to readers being able to check the calculation decisions of the authors. But how to achieve full data archiving? This is the raw data archiving challenge, in size and need for correct metadata. Processed diffraction data and final derived molecular coordinates archiving in crystallography have achieved an exemplary state of the art relative to most fields. One can credit IUCr with developing exemplary peer review procedures, of narrative, underpinning structure factors and coordinate data and validation report, through its checkcif development and submission system introduced for Acta Cryst. C and subsequently developed for its other chemistry journals. The crystallographic databases likewise have achieved amazing success and sustainability these last 50 years or so. The wider science data scene is celebrating the FAIR data accord, namely, that data be Findable, Accessible, Interoperable, and Reusable [Wilkinson et al., “Comment: The FAIR guiding principles for scientific data management and stewardship,” Sci. Data 3, 160018 (2016)]. Some social scientists also emphasize more than FAIR being needed, the data should be “FACT,” which is an acronym meaning Fair, Accurate, Confidential, and Transparent [van der Aalst et al., “Responsible data science,” Bus Inf. Syst. Eng. 59(5), 311–313 (2017)], this being the issue of ensuring reproducibility not just reusability. (Confidentiality of data not likely being relevant to our data obviously.) Acta Cryst. B, C, E, and IUCrData are the closest I know to being both FACT and FAIR where I repeat for due emphasis: the narrative, the automatic “general” validation checks, and the underpinning data are checked thoroughly by subject specialists (i.e., the specialist referees). IUCr Journals are also the best that I know of for encouraging and then expediting the citation of the DOI for a raw diffraction dataset in a publication; examples can be found in IUCrJ, Acta Cryst D, and Acta Cryst F. The wish for a checkcif for raw diffraction data has been championed by the IUCr Diffraction Data Deposition Working Group and its successor, the IUCr Committee on Data.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5124439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46383757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time resolved transient circular dichroism spectroscopy using synchrotron natural polarization","authors":"François Auvray, D. Dennetiere, A. Giuliani, F. Jamme, F. Wien, B. Nay, S. Zirah, F. Polack, C. Menneglier, B. Lagarde, J. Hirst, M. Réfrégiers","doi":"10.1063/1.5120346","DOIUrl":"https://doi.org/10.1063/1.5120346","url":null,"abstract":"Ultraviolet (UV) synchrotron radiation circular dichroism (SRCD) spectroscopy has made an important contribution to the determination and understanding of the structure of bio-molecules. In this paper, we report an innovative approach that we term time-resolved SRCD (tr-SRCD), which overcomes the limitations of current broadband UV SRCD setups. This technique allows accessing ultrafast time scales (down to nanoseconds), previously measurable only by other methods, such as infrared (IR), nuclear magnetic resonance (NMR), fluorescence and absorbance spectroscopies, and small angle X-ray scattering (SAXS). The tr-SRCD setup takes advantage of the natural polarization of the synchrotron radiation emitted by a bending magnet to record broadband UV CD faster than any current SRCD setup, improving the acquisition speed from 10 mHz to 130 Hz and the accessible temporal resolution by several orders of magnitude. We illustrate the new approach by following the isomer concentration changes of an azopeptide after a photoisomerization. This breakthrough in SRCD spectroscopy opens up a wide range of potential applications to the detailed characterization of biological processes, such as protein folding and protein-ligand binding.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5120346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42006560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hole dynamics in a photovoltaic donor-acceptor couple revealed by simulated time-resolved X-ray absorption spectroscopy","authors":"Khadijeh Khalili, L. Inhester, C. Arnold, R. Welsch, J. W. Andreasen, R. Santra","doi":"10.1063/1.5097653","DOIUrl":"https://doi.org/10.1063/1.5097653","url":null,"abstract":"Theoretical and experimental methodologies that can characterize electronic and nuclear dynamics, and the coupling between the two, are needed to understand photoinduced charge transfer in molecular building blocks used in organic photovoltaics. Ongoing developments in ultrafast pump-probe techniques such as time-resolved X-ray absorption spectroscopy, using an X-ray free electron laser in combination with an ultraviolet femtosecond laser, present desirable probes of coupled electronic and nuclear dynamics. In this work, we investigate the charge transfer dynamics of a donor-acceptor pair, which is widely used as a building block in low bandgap block copolymers for organic photovoltaics. We simulate the dynamics of the benzothiadiazole-thiophene molecule upon photoionization with a vacuum ultraviolet (VUV) pulse and study the potential of probing the subsequent charge dynamics using time-resolved X-ray absorption spectroscopy. The photoinduced dynamics are calculated using on-the-fly nonadiabatic molecular dynamics simulations based on Tully's Fewest Switches Surface Hopping approach. We calculate the X-ray absorption spectrum as a function of time after ionization at the Hartree-Fock level. The changes in the time-resolved X-ray absorption spectrum at the sulfur K-edge reveal the ultrafast charge carrier dynamics in the molecule occurring on a femtosecond time scale. These theoretical findings anticipate that ultrafast time-resolved X-ray absorption spectroscopy using an X-ray probe in combination with a VUV pump offers a new approach to investigate the detailed dynamics of organic photovoltaic materials.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5097653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46409219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is radiation damage the limiting factor in high-resolution single particle imaging with X-ray free-electron lasers?","authors":"C. Östlin, N. Tîmneanu, C. Caleman, A. V. Martin","doi":"10.1063/1.5098309","DOIUrl":"https://doi.org/10.1063/1.5098309","url":null,"abstract":"The prospect of single particle imaging with atomic resolution is one of the scientific drivers for the development of X-ray free-electron lasers. The assumption since the beginning has been that damage to the sample caused by intense X-ray pulses is one of the limiting factors for achieving subnanometer X-ray imaging of single particles and that X-ray pulses need to be as short as possible. Based on the molecular dynamics simulations of proteins in X-ray fields of various durations (5 fs, 25 fs, and 50 fs), we show that the noise in the diffracted signal caused by radiation damage is less than what can be expected from other sources, such as sample inhomogeneity and X-ray shot-to-shot variations. These findings show a different aspect of the feasibility of high-resolution single particle imaging using free-electron lasers, where employing X-ray pulses of longer durations could still provide a useful diffraction signal above the noise due to the Coulomb explosion.","PeriodicalId":48683,"journal":{"name":"Structural Dynamics-Us","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1063/1.5098309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45777561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"物理与天体物理","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}