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Chemical crystallography

Stephen Bh Kent
A racemic protein mixture can be used to form centrosymmetric crystals for structure determination by X-ray diffraction. Both the unnatural d-protein and the corresponding natural l-protein are made by total chemical synthesis based on native chemical ligation-chemoselective condensation of unprotected synthetic peptide segments. Racemic protein crystallography is important for structure determination of the many natural protein molecules that are refractory to crystallization. Racemic mixtures facilitate the crystallization of recalcitrant proteins, and give diffraction-quality crystals...
April 4, 2018: Current Opinion in Chemical Biology
Jinlan Gao, Hao Wang, Qipeng Yuan, Yue Feng
Photosynthesis converts solar energy into chemical energy to sustain all life on earth by providing oxygen and food, and controlling the atmospheric carbon dioxide. During this process, the water-splitting and oxygen-evolving reaction is catalyzed by photosystem II (PSII), while photosystem I (PSI) generates the reducing power for the reduction of NADP+ to NADPH. Together with their peripheral light-harvesting complexes (LHCs), photosystems function as multisubunit supercomplexes located in the thylakoid membranes of cyanobacteria, algae, and plants...
2018: Frontiers in Plant Science
Rebecca Freilich, Taylor Arhar, Jennifer L Abrams, Jason E Gestwicki
Molecular chaperones play a central role in protein homeostasis (a.k.a. proteostasis) by balancing protein folding, quality control, and turnover. To perform these diverse tasks, chaperones need the malleability to bind nearly any "client" protein and the fidelity to detect when it is misfolded. Remarkably, these activities are carried out by only ∼180 dedicated chaperones in humans. How do a relatively small number of chaperones maintain cellular and organismal proteostasis for an entire proteome? Furthermore, once a chaperone binds a client, how does it "decide" what to do with it? One clue comes from observations that individual chaperones engage in protein-protein interactions (PPIs)-both with each other and with their clients...
April 3, 2018: Accounts of Chemical Research
Matteo Rossi Sebastiano, Bradley C Doak, Maria Backlund, Vasanthanathan Poongavanam, Björn Over, Giuseppe Ermondi, Giulia Caron, Pär Matsson, Jan Kihlberg
Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds' minimum solvent-accessible 3D polar surface areas (PSA), while aqueous solubility depended less on the specific 3D conformation...
April 2, 2018: Journal of Medicinal Chemistry
Daisuke Imahori, Takahiro Matsumoto, Naoto Kojima, Tomohiro Hasei, Megumi Sumii, Taishi Sumida, Masayuki Yamashita, Tetsushi Watanabe
Two novel and two known compounds, 4-quinolylaldoxime and indole-3-aldehyde, were isolated from a reaction mixture consisting of D-glucose and L-tryptophan at physiological temperature and pH. The chemical structures of the two novel compounds were elucidated by spectroscopic analysis such as X-ray crystallography. One of the novel compound and the indole-3-aldehyde showed mutagenicity toward Salmonella typhimurium YG1024 with S9 mix. Furthermore, 4-quinolylaldoxime was detected from streptozotocin-induced diabetic rat plasma by LC-MS/MS analysis; however, the isolated compounds were not detected in rat diet extracts...
2018: Chemical & Pharmaceutical Bulletin
Peng-Cheng Duan, Dennis-Helmut Manz, Sebastian Dechert, Serhiy Demeshko, Franc Meyer
Dioxygen activation at nickel complexes is much less studied than for the biologically more relevant iron or copper systems but promises new reactivity patterns because of the distinct coordination chemistry of nickel. Here we report that a pyrazolate-based dinickel(II) dihydride complex [KL(Ni-H)2 ] (1a) smoothly reacts with O2 via reductive H2 elimination to give the μ-1,2-peroxo dinickel(II) complex [KLNi2 (O2 )] (2a) and, after treatment with dibenzo[18]-crown-6, the separated ion pair [K(DB18C6)][LNi2 (O2 )] (2b); these are the first μ-1,2-peroxo dinickel intermediates to be characterized by X-ray diffraction...
March 29, 2018: Journal of the American Chemical Society
Shashank P Katiyar, Vidhi Malik, Anjani Kumari, Kamya Singh, Durai Sundar
Fragment-based drug design strategies have been used in drug discovery since it was first demonstrated using experimental structural biology techniques such as nuclear magnetic resonance (NMR) and X-ray crystallography. The underlying idea is that existing or new chemical entities with known desirable properties may serve both as tool compounds and as starting points for hit-to-lead expansion. Despite the recent advancements, there remain challenges to overcome, such as assembly of the synthetically feasible structures, development of scoring functions to correlate structure and their activities, and fine tuning of the promising molecules...
2018: Methods in Molecular Biology
Appu K Singh, Luke L McGoldrick, Kei Saotome, Alexander I Sobolevsky
Transient receptor potential (TRP) ion channels are molecular sensors of a large variety of stimuli including temperature, mechanical stress, voltage, small molecules including capsaicin and menthol, and lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2 ). Since the same TRP channels may respond to different physical and chemical stimuli, they can serve as signal integrators. Many TRP channels are calcium permeable and contribute to Ca2+ homeostasis and signaling. Although the TRP channel family was discovered decades ago, only recently have the structures of many of these channels been solved, largely by cryo-electron microscopy (cryo-EM)...
March 28, 2018: Channels
Judith E Unterlass, Arnaud Baslé, Timothy J Blackburn, Julie Tucker, Céline Cano, Martin E M Noble, Nicola J Curtin
3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in PHGDH -amplified breast cancer. Knockdown caused reduced proliferation in the PHGDH -amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected...
March 2, 2018: Oncotarget
Martin Köhler, Christoph Neff, Camilo Perez, Cyrill Brunner, Els Pardon, Jan Steyaert, Gisbert Schneider, Kaspar P Locher, Renato Zenobi
The application of nanobodies as binding partners for structure stabilization in protein x-ray crystallography is taking an increasingly important role in structural biology. However, the addition of nanobodies to the crystallization matrices might complicate the optimization of the crystallization process, which is why analytical techniques to screen and characterize suitable nanobodies are useful. Here, we show how chemical cross-linking combined with high-mass matrix-assisted laser/desorption ionization mass spectrometry can be employed as a fast screening technique to determine binding specificities of intact nanobody•membrane protein complexes...
March 21, 2018: Analytical Chemistry
Min Liu, Xu-Feng Yang, Hai-Bin Zhu, Bao-Sheng Di, Yue Zhao
A Keggin-type polyoxometalate (POM)-templated metal-organic framework, [Cd(TTPB-4)(DMF)3]4[PMo12O40]2[HPMo12O40]·6DMF·4H2O (1), based on a newly designed linker of TTPB-4 [TTPB-4 = 1,3,5-tris(4-(4H-1,2,4-triazol-4-yl)phenyl)benzene], has been hydrothermally synthesized and characterized using IR, XRD, TGA, UV-Vis and photoluminescence spectra. Single-crystal X-ray crystallography reveals that 1 represents a unique POM-templated four-fold interpenetrated 3-D coordination network. The POM-templated MOF of 1 exhibits strong chemical stability that can withstand aqueous solutions of various pH-values (2-10)...
March 21, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Junghyun L Suh, Brian Watts, Jacob I Stuckey, Jacqueline L Norris-Drouin, Stephanie H Cholensky, Bradley M Dickson, Yi An, Sebastian Mathea, Eidarus Salah, Stefan Knapp, Abid Khan, Alexander T Adams, Brian D Strahl, Cari A Sagum, Mark T Bedford, Lindsey I James, Dmitri B Kireev, Stephen V Frye
Multivalent binding is an efficient means to enhance the affinity and specificity of chemical probes targeting multi-domain proteins in order to study their function and role in disease. While the theory of multivalent binding is straightforward, physical and structural characterization of bivalent binding encounters multiple technical difficulties. We present a case study where a combination of experimental techniques and computational simulations was used to comprehensively characterize the binding and structure-affinity relationships for a series of Bromosporine-based bivalent bromodomain ligands with a bivalent protein, Transcription Initiation Factor TFIID subunit 1 (TAF1)...
March 20, 2018: Biochemistry
Nizaá Jiménez-Arroyo, Paloma C Gil-Rodríguez, Adelaida Díaz-Vilchis, Sonia P Rojas-Trejo, Enrique Rudiño-Piñera
Understanding Peroxidase (PRXs) enzymatic diversity and functional significance from a three-dimensional point of view is a key point for structural and mechanistic studies. In this context, Zo-peroxidase (ZoPrx) a member of the class III peroxidases and secreted by plants, differs from all previously described PRXs because of its remarkable catalytic stability in the presence of hydrogen peroxide. In this work, we present the crystallographic structure of ZoPrx isolated from Japanese radish, at 2.05 Å resolution...
March 2018: Biochemistry and Biophysics Reports
Evgenia N Nikolova, Robyn L Stanfield, Jane Dyson, Peter E Wright
Many eukaryotic transcription factors recognize the epigenetic marker 5-methylcytosine (mC) at CpG sites in DNA. Despite their structural diversity, methyl-CpG-binding proteins (MBPs) share a common mode of recognition of mC methyl groups that involves hydrophobic pockets and weak hydrogen bonds of the CH---O type. The zinc finger protein Kaiso possesses a remarkably high specificity for methylated over unmethylated CpG sites. A key contribution to this specificity is provided by glutamate 535 (E535), which is optimally positioned to form multiple interactions with mCpG, including direct CH---O hydrogen bonds...
March 16, 2018: Biochemistry
Rémi Patouret, Christelle Doebelin, Ruben D Garcia-Ordonez, Mi Ra Chang, Claudia Ruiz, Michael D Cameron, Patrick R Griffin, Theodore M Kamenecka
Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORβ inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORβ-selective modulators...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Graeme Winter, David G Waterman, James M Parkhurst, Aaron S Brewster, Richard J Gildea, Markus Gerstel, Luis Fuentes-Montero, Melanie Vollmar, Tara Michels-Clark, Iris D Young, Nicholas K Sauter, Gwyndaf Evans
The DIALS project is a collaboration between Diamond Light Source, Lawrence Berkeley National Laboratory and CCP4 to develop a new software suite for the analysis of crystallographic X-ray diffraction data, initially encompassing spot finding, indexing, refinement and integration. The design, core algorithms and structure of the software are introduced, alongside results from the analysis of data from biological and chemical crystallography experiments.
February 1, 2018: Acta Crystallographica. Section D, Structural Biology
Laurent Batiste, Andrea Unzue, Aymeric Dolbois, Fabrice Hassler, Xuan Wang, Nicholas Deerain, Jian Zhu, Dimitrios Spiliotopoulos, Cristina Nevado, Amedeo Caflisch
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment...
February 28, 2018: ACS Central Science
P E Mandelare, D A Adpressa, E N Kaweesa, L N Zakharov, S Loesgen
The genetically encoded, small-molecule chemical diversity of filamentous fungi is still largely unexplored and represents an attractive source for the discovery of new compounds. Here we report the production of new chlorinated bianthrones from coculture of two different developmental stages, or morphs, of a marine alga-derived Aspergillus alliaceus (teleomorph: Petromyces alliaceus) strain. The vegetative stage (asexual morph) can be separated from the morph that switched to sexual development (sclerotial morph); both produce distinct secondary metabolite patterns...
March 8, 2018: Journal of Natural Products
Per Rogne, Marie Rosselin, Christin Grundström, Christian Hedberg, Uwe H Sauer, Magnus Wolf-Watz
Enzymatic substrate selectivity is critical for the precise control of metabolic pathways. In cases where chemically related substrates are present inside cells, robust mechanisms of substrate selectivity are required. Here, we report the mechanism utilized for catalytic ATP versus GTP selectivity during adenylate kinase (Adk) -mediated phosphorylation of AMP. Using NMR spectroscopy we found that while Adk adopts a catalytically competent and closed structural state in complex with ATP, the enzyme is arrested in a catalytically inhibited and open state in complex with GTP...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Colin E Correnti, Mesfin M Gewe, Christopher Mehlin, Ashok D Bandaranayake, William A Johnsen, Peter B Rupert, Mi-Youn Brusniak, Midori Clarke, Skyler E Burke, Willem De Van Der Schueren, Kristina Pilat, Shanon M Turnbaugh, Damon May, Alex Watson, Man Kid Chan, Christopher D Bahl, James M Olson, Roland K Strong
Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high-throughput expression, screening and large-scale production of these peptides: 46 were successfully produced in multimilligram quantities, and >600 more were deemed expressible through stringent screening criteria...
February 26, 2018: Nature Structural & Molecular Biology
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