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218 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
	Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension Apirat Chaikuad , Chancievan Thangaratnarajah , Frank Von Delft , Alex N. Bullock Scientific Reports 9 DOI: 10.1038/s41598-019-54830-7 Open Access Show Abstract ▼ Abstract: Bone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-β (TGF-β) family that control embryonic patterning, as well as tissue development and homeostasis. Loss of function mutations in the type II BMP receptor BMPR2 are the leading cause of pulmonary arterial hypertension (PAH), a rare disease of vascular occlusion that leads to high blood pressure in the pulmonary arteries. To understand the structural consequences of these mutations, we determined the crystal structure of the human wild-type BMPR2 kinase domain at 2.35 Å resolution. The structure revealed an active conformation of the catalytic domain that formed canonical interactions with the bound ligand Mg-ADP. Disease-associated missense mutations were mapped throughout the protein structure, but clustered predominantly in the larger kinase C-lobe. Modelling revealed that the mutations will destabilize the protein structure by varying extents consistent with their previously reported functional heterogeneity. The most severe mutations introduced steric clashes in the hydrophobic protein core, whereas those found on the protein surface were less destabilizing and potentially most favorable for therapeutic rescue strategies currently under clinical investigation.	Dec 2019
	Peculiarities of pseudogap in Y0.95Pr0.05Ba2Cu3O7−δ single crystals under pressure up to 1.7 GPa A. L. Solovjov , L. V. Omelchenko , E. V. Petrenko , R. V. Vovk , V. V. Khotkevych , A. Chroneos Scientific Reports 9 DOI: 10.1038/s41598-019-55959-1 Open Access Show Abstract ▼ Abstract: The effect of hydrostatic pressure up to P = 1.7 GPa on the fluctuation conductivity σ′(T) and pseudogap ∆(T) in Y0.95Pr0.05Ba2Cu3O7−δ single crystal with critical temperature Тс = 85.2 K (at P = 0) was investigated. The application of pressure leads to the increase in Tc with dTc/dP = +1.82 K∙GPa−1 while the resistance decreases as dlnρ(100 K)/dP = −(10.5 ± 0.2) %∙GPa−1. Regardless of the pressure, in the temperature interval from Tc to T0 (~88 K at P = 0) the behaviour of σ′(T) is well described by the Aslamazov – Larkin (AL – 3D) fluctuation theory, and above the T0 by the Lawrence – Doniach theory (LD). The Maki-Thompson (MT – 2D) fluctuation contribution is not observed. This indicates the presence of structural defects in the sample induced by Pr. Here it is determined for the first time that when the pressure is applied to the Y1−xPrxBa2Cu3O7−δ single crystal, the pseudogap increases as dlnΔ/dP = 0.17 GPa–1.	Dec 2019
I09-Surface and Interface Structural Analysis	Surface chemistry dependence on aluminum doping in Ni-rich LiNi0.8Co0.2−yAlyO2 cathodes Zachary W. Lebens-higgins , David M. Halat , Nicholas V. Faenza , Matthew J. Wahila , Manfred Mascheck , Tomas Wiell , Susanna K. Eriksson , Paul Palmgren , Jose Rodriguez , Fadwa Badway , Nathalie Pereira , Glenn G. Amatucci , Tien-lin Lee , Clare P. Grey , Louis F. J. Piper Scientific Reports 9 DOI: 10.1038/s41598-019-53932-6 Diamond Proposal Number(s): [22250, 22148] Open Access Show Abstract ▼ Abstract: Aluminum is a common dopant across oxide cathodes for improving the bulk and cathode-electrolyte interface (CEI) stability. Aluminum in the bulk is known to enhance structural and thermal stability, yet the exact influence of aluminum at the CEI remains unclear. To address this, we utilized a combination of X-ray photoelectron and absorption spectroscopy to identify aluminum surface environments and extent of transition metal reduction for Ni-rich LiNi0.8Co0.2−yAlyO2 (0%, 5%, or 20% Al) layered oxide cathodes tested at 4.75 V under thermal stress (60 °C). For these tests, we compared the conventional LiPF6 salt with the more thermally stable LiBF4 salt. The CEI layers are inherently different between these two electrolyte salts, particularly for the highest level of Al-doping (20%) where a thicker (thinner) CEI layer is found for LiPF6 (LiBF4). Focusing on the aluminum environment, we reveal the type of surface aluminum species are dependent on the electrolyte salt, as Al-O-F- and Al-F-like species form when using LiPF6 and LiBF4, respectively. In both cases, we find cathode-electrolyte reactions drive the formation of a protective Al-F-like barrier at the CEI in Al-doped oxide cathodes.	Dec 2019
I04-1-Macromolecular Crystallography (fixed wavelength)	Biochemical and structural insights into the cytochrome P450 reductase from Candida tropicalis Ana C. Ebrecht , Naadia Van Der Bergh , Susan T. L. Harrison , Martha S. Smit , B. Trevor Sewell , Diederik J. Opperman Scientific Reports 9 DOI: 10.1038/s41598-019-56516-6 Diamond Proposal Number(s): [18938] Open Access Show Abstract ▼ Abstract: Cytochrome P450 reductases (CPRs) are diflavin oxidoreductases that supply electrons to type II cytochrome P450 monooxygenases (CYPs). In addition, it can also reduce other proteins and molecules, including cytochrome c, ferricyanide, and different drugs. Although various CPRs have been functionally and structurally characterized, the overall mechanism and its interaction with different redox acceptors remain elusive. One of the main problems regarding electron transfer between CPRs and CYPs is the so-called “uncoupling”, whereby NAD(P)H derived electrons are lost due to the reduced intermediates’ (FAD and FMN of CPR) interaction with molecular oxygen. Additionally, the decay of the iron-oxygen complex of the CYP can also contribute to loss of reducing equivalents during an unproductive reaction cycle. This phenomenon generates reactive oxygen species (ROS), leading to an inefficient reaction. Here, we present the study of the CPR from Candida tropicalis (CtCPR) lacking the hydrophobic N-terminal part (Δ2–22). The enzyme supports the reduction of cytochrome c and ferricyanide, with an estimated 30% uncoupling during the reactions with cytochrome c. The ROS produced was not influenced by different physicochemical conditions (ionic strength, pH, temperature). The X-ray structures of the enzyme were solved with and without its cofactor, NADPH. Both CtCPR structures exhibited the closed conformation. Comparison with the different solved structures revealed an intricate ionic network responsible for the regulation of the open/closed movement of CtCPR.	Dec 2019
B21-High Throughput SAXS	Nano-encapsulated Escherichia coli divisome anchor ZipA, and in complex with FtsZ Sarah C. Lee , Richard Collins , Yu-pin Lin , Mohammed Jamshad , Claire Broughton , Sarah A. Harris , Benjamin S. Hanson , Cecilia Tognoloni , Rosemary A. Parslow , Ann E. Terry , Alison Rodger , Corinne J. Smith , Karen J. Edler , Robert Ford , David I. Roper , Timothy R. Dafforn Scientific Reports 9 DOI: 10.1038/s41598-019-54999-x Diamond Proposal Number(s): [9727] Open Access Show Abstract ▼ Abstract: The E. coli membrane protein ZipA, binds to the tubulin homologue FtsZ, in the early stage of cell division. We isolated ZipA in a Styrene Maleic Acid lipid particle (SMALP) preserving its position and integrity with native E. coli membrane lipids. Direct binding of ZipA to FtsZ is demonstrated, including FtsZ fibre bundles decorated with ZipA. Using Cryo-Electron Microscopy, small-angle X-ray and neutron scattering, we determine the encapsulated-ZipA structure in isolation, and in complex with FtsZ to a resolution of 1.6 nm. Three regions can be identified from the structure which correspond to, SMALP encapsulated membrane and ZipA transmembrane helix, a separate short compact tether, and ZipA globular head which binds FtsZ. The complex extends 12 nm from the membrane in a compact structure, supported by mesoscale modelling techniques, measuring the movement and stiffness of the regions within ZipA provides molecular scale analysis and visualisation of the early divisome.	Dec 2019
Krios I-Titan Krios I at Diamond	The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism Lucía Quintana-gallardo , Jaime Martin-benito , Miguel Marcilla , Guadalupe Espadas , Eduard Sabidó , José María Valpuesta Scientific Reports 9 DOI: 10.1038/s41598-019-41060-0 Diamond Proposal Number(s): [16943, 15997] Open Access Show Abstract ▼ Abstract: Some molecular chaperones are involved not only in assisting the folding of proteins but also, given appropriate conditions, in their degradation. This is the case for Hsp70 and Hsp90 which, in concert with the cochaperone CHIP, direct their bound substrate to degradation through ubiquitination. We generated complexes between the chaperones (Hsp70 or Hsp90), the cochaperone CHIP and, as substrate, a p53 variant containing the GST protein (p53-TMGST). Both ternary complexes (Hsp70:p53-TMGST:CHIP and Hsp90:p53-TMGST:CHIP) ubiquitinated the substrate at a higher efficiency than in the absence of the chaperones. The 3D structures of the two complexes, obtained using a combination of cryoelectron microscopy and crosslinking mass spectrometry, showed the substrate located between the chaperone and the cochaperone, suggesting a ubiquitination mechanism in which the chaperone-bound substrate is presented to CHIP. These complexes are inherently flexible, which is important for the ubiquitination process.	Dec 2019
I24-Microfocus Macromolecular Crystallography	Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors Gerson S. Profeta , Caio V. Dos Reis , André Da S. Santiago , Paulo H. C. Godoi , Angela M. Fala , Carrow I. Wells , Roger Sartori , Anita P. T. Salmazo , Priscila Z. Ramos , Katlin B. Massirer , Jonathan M. Elkins , David H. Drewry , Opher Gileadi , Rafael M. Counago Scientific Reports 9 DOI: 10.1038/s41598-019-52795-1 Diamond Proposal Number(s): [16171] Open Access Show Abstract ▼ Abstract: Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this protein kinase. Moreover, CAMKK2 and its closest human homolog, CAMKK1, are thought to have overlapping biological roles. Here we present six new co-structures of potent ligands bound to CAMKK2 identified from a library of commercially-available kinase inhibitors. Enzyme assays confirmed that most of these compounds are equipotent inhibitors of both human CAMKKs and isothermal titration calorimetry (ITC) revealed that binding to some of these molecules to CAMKK2 is enthalpy driven. We expect our results to advance current efforts to discover small molecule kinase inhibitors selective to each human CAMKK.	Nov 2019
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation Pooja Sharma , Robert Mahen , Maxim Rossmann , Jamie E. Stokes , Bryn Hardwick , David J. Huggins , Amy Emery , Dominique L. Kunciw , Marko Hyvonen , David R. Spring , Grahame J. Mckenzie , Ashok R. Venkitaraman Scientific Reports 9 DOI: 10.1038/s41598-019-50702-2 Diamond Proposal Number(s): [7141, 9537] Open Access Show Abstract ▼ Abstract: The human polo-like kinase PLK1 coordinates mitotic chromosome segregation by phosphorylating multiple chromatin- and kinetochore-binding proteins. How PLK1 activity is directed to specific substrates via phosphopeptide recognition by its carboxyl-terminal polo-box domain (PBD) is poorly understood. Here, we combine molecular, structural and chemical biology to identify a determinant for PLK1 substrate recognition that is essential for proper chromosome segregation. We show that mutations ablating an evolutionarily conserved, Tyr-lined pocket in human PLK1 PBD trigger cellular anomalies in mitotic progression and timing. Tyr pocket mutations selectively impair PLK1 binding to the kinetochore phosphoprotein substrate PBIP1, but not to the centrosomal substrate NEDD1. Through a structure-guided approach, we develop a small-molecule inhibitor, Polotyrin, which occupies the Tyr pocket. Polotyrin recapitulates the mitotic defects caused by mutations in the Tyr pocket, further evidencing its essential function, and exemplifying a new approach for selective PLK1 inhibition. Thus, our findings support a model wherein substrate discrimination via the Tyr pocket in the human PLK1 PBD regulates mitotic chromosome segregation to preserve genome integrity.	Nov 2019
I13-2-Diamond Manchester Imaging	Tracking capsule activation and crack healing in a microcapsule-based self-healing polymer S. A. Mcdonald , S. B. Coban , N. R. Sottos , P. J. Withers Scientific Reports 9 DOI: 10.1038/s41598-019-54242-7 Diamond Proposal Number(s): [4022] Open Access Show Abstract ▼ Abstract: Structural polymeric materials incorporating a microencapsulated liquid healing agent demonstrate the ability to autonomously heal cracks. Understanding how an advancing crack interacts with the microcapsules is critical to optimizing performance through tailoring the size, distribution and density of these capsules. For the first time, time-lapse synchrotron X-ray phase contrast computed tomography (CT) has been used to observe in three-dimensions (3D) the dynamic process of crack growth, microcapsule rupture and progressive release of solvent into a crack as it propagates and widens, providing unique insights into the activation and repair process. In this epoxy self-healing material, 150 µm diameter microcapsules within 400 µm of the crack plane are found to rupture and contribute to the healing process, their discharge quantified as a function of crack propagation and distance from the crack plane. Significantly, continued release of solvent takes place to repair the crack as it grows and progressively widens.	Nov 2019
I15-Extreme Conditions	Thermal equation of state of ruthenium characterized by resistively heated diamond anvil cell Simone Anzellini , Daniel Errandonea , Claudio Cazorla , Simon Macleod , Virginia Monteseguro , Silvia Boccato , Enrico Bandiello , Daniel Diaz Anichtchenko , Catalin Popescu , Christine M. Beavers Scientific Reports 9 DOI: 10.1038/s41598-019-51037-8 Diamond Proposal Number(s): [23122] Open Access Show Abstract ▼ Abstract: The high-pressure and high-temperature structural and chemical stability of ruthenium has been investigated via synchrotron X-ray diffraction using a resistively heated diamond anvil cell. In the present experiment, ruthenium remains stable in the hcp phase up to 150 GPa and 960 K. The thermal equation of state has been determined based upon the data collected following four different isotherms. A quasi-hydrostatic equation of state at ambient temperature has also been characterized up to 150 GPa. The measured equation of state and structural parameters have been compared to the results of ab initio simulations performed with several exchange-correlation functionals. The agreement between theory and experiments is generally quite good. Phonon calculations were also carried out to show that hcp ruthenium is not only structurally but also dynamically stable up to extreme pressures. These calculations also allow the pressure dependence of the Raman-active E2g mode and the silent B1g mode of Ru to be determined.	Oct 2019

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