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Chemical crystallography

Bobo Dang, Rong Shen, Tomoya Kubota, Kalyaneswar Mandal, Francisco Bezanilla, Benoit Roux, Stephen B H Kent
ShK toxin is a cysteine-rich 35-residue protein ion-channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side-chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo-Thr or an allo-Ile residue...
February 14, 2017: Angewandte Chemie
Juan R Perilla, Gongpu Zhao, Manman Lu, Jiying Ning, Guangjin Hou, In-Ja L Byeon, Angela M Gronenborn, Tatyana Polenova, Peijun Zhang
Single particle cryoEM has emerged as a powerful method for structure determination of proteins and complexes, complementing X-ray crystallography and NMR spectroscopy. Yet, for many systems, the resolution of cryoEM density map has been limited to 4-6 Å, which only allows for resolving bulky amino acids side chains, thus hindering accurate model building from the density map. On the other hand, experimental chemical shifts (CS) from solution and solid state MAS NMR spectra provide atomic level data for each amino acid within a molecule or a complex; however, structure determination of large complexes and assemblies based on NMR data alone remains challenging...
February 9, 2017: Journal of Physical Chemistry. B
Ben Bax, Chun Wa Chung, Colin Edge
There are more H atoms than any other type of atom in an X-ray crystal structure of a protein-ligand complex, but as H atoms only have one electron they diffract X-rays weakly and are `hard to see'. The positions of many H atoms can be inferred by our chemical knowledge, and such H atoms can be added with confidence in `riding positions'. For some chemical groups, however, there is more ambiguity over the possible hydrogen placements, for example hydroxyls and groups that can exist in multiple protonation states or tautomeric forms...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
Fei Long, Robert A Nicholls, Paul Emsley, Saulius Graǽulis, Andrius Merkys, Antanas Vaitkus, Garib N Murshudov
The program AceDRG is designed for the derivation of stereochemical information about small molecules. It uses local chemical and topological environment-based atom typing to derive and organize bond lengths and angles from a small-molecule database: the Crystallography Open Database (COD). Information about the hybridization states of atoms, whether they belong to small rings (up to seven-membered rings), ring aromaticity and nearest-neighbour information is encoded in the atom types. All atoms from the COD have been classified according to the generated atom types...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
Alexandre Martinez, Dawei Zhang, Laure Guy, Jean-Pierre Dutasta, James Robert Cochrane, Sebastiano Di Pietro, Heinz Gornitzka
A class of hemicryptophane cages that adopt imploded conformations in solution and in the solid state is described and studied by NMR and X-ray crystallography. We show that the degree of collapse of the molecular cavity can be controlled by changing the stereochemistry of the chiral elements of the hemicryptophanes, leading to a modulation of their physical and chemical properties. Upon the binding of an oxidovanadium unit, the collapsed molecular cavity can inflate to give an expanded conformation. Removal of the vanadium core by an ancillary complexing ligand restores the initial folded structure...
February 3, 2017: Chemistry: a European Journal
Yongsoo Yang, Chien-Chun Chen, M C Scott, Colin Ophus, Rui Xu, Alan Pryor, Li Wu, Fan Sun, Wolfgang Theis, Jihan Zhou, Markus Eisenbach, Paul R C Kent, Renat F Sabirianov, Hao Zeng, Peter Ercius, Jianwei Miao
Perfect crystals are rare in nature. Real materials often contain crystal defects and chemical order/disorder such as grain boundaries, dislocations, interfaces, surface reconstructions and point defects. Such disruption in periodicity strongly affects material properties and functionality. Despite rapid development of quantitative material characterization methods, correlating three-dimensional (3D) atomic arrangements of chemical order/disorder and crystal defects with material properties remains a challenge...
February 1, 2017: Nature
Albert Hofstetter, Lyndon Emsley
We propose a method to quantify positional uncertainties in crystal structures determined by chemical-shift-based NMR crystallography. The method combines molecular dynamics simulations and density functional theory calculations with experimental and computational chemical shift uncertainties. In this manner we find the average positional accuracy as well as the isotropic and anisotropic positional accuracy associated with each atom in a crystal structure determined by NMR crystallography. The approach is demonstrated on the crystal structures of cocaine, flutamide, flufenamic acid, the K salt of penicillin G, and form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butylpyrazol-1-yl]benzoic acid (AZD8329)...
February 8, 2017: Journal of the American Chemical Society
Piotr Kuś, Joachim Kusz, Maria Książek, Ewelina Pieprzyca, Marcin Rojkiewicz
Comprehensive chemical characterization for two cathinone derivatives, N-ethyl-2-amino-1-phenylpropan-1-one (ethcathinone) hydrochloride and N-ethyl-2-amino-1-(4-chlorophenyl)-propan-1-one (4-chloroethcathinone, 4-CEC) hydrochloride, in material seized by drug enforcement agencies was performed by nuclear magnetic resonance (NMR) spectroscopy, infrared spectroscopy, gas chromatography-mass spectrometry in positive electron ionization mode, liquid chromatography-mass spectrometry in positive electrospray ionization mode and X-ray crystallography...
2017: Forensic Toxicology
Zexin Jin, Yew Chin Teo, Nicolo G Zulaybar, Matthew D Smith, Yan Xia
The juxtaposition of fused cyclobutadienoid (CBD) with benzenoid creates intriguing alternating antiaromatic and aromatic conjugation. Synthetic accessibility of such molecules, however, has been challenging and limited in scope. We report a modular and streamlined synthetic strategy to access a large variety of polycyclic conjugated hydrocarbons with fused CBD. Synthesis was achieved through efficient palladium-catalyzed C-H activated annulation between abundant aryl bromides and oxanorbornenes, followed by aromatization under acidic conditions...
January 26, 2017: Journal of the American Chemical Society
Agnieszka Gunia-Krzyżak, Ewa Żesławska, Florence Bareyre, Wojciech Nitek, Anna M Waszkielewicz, Henryk Marona
A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, additionally thermal analysis showed that it exists in one crystalline form...
January 18, 2017: Chemical Biology & Drug Design
Helge Klare, Jörg M Neudörfl, Simon D Brandt, Elisabeth Mischler, Sigrid Meier-Giebing, Kathrin Deluweit, Folker Westphal, Tim Laussmann
Six collected phenidates, i.e. 4-methylmethylphenidate, 3,4-dichloromethylphenidate, ethylphenidate, 3,4-dichloroethylphenidate, ethylnaphthidate and N-benzyl-ethylphenidate were fully characterized by means of X-ray, NMR, GC-MS, ESI-MS(2) , ATR-FT-IR and GC solid-state IR analysis. Crystallography revealed the exclusive presence of the threo-configuration. Steric crowding induced by N-benzyl substitution at the piperidine moiety prompted an adoption of an unexpected axial positioning of substituents on the piperidine moiety in the crystal state as opposed to the exclusive equatorial positioning encountered in N-unsubstituted phenidate analogs...
January 9, 2017: Drug Testing and Analysis
Feng Yu, Shengbo Yao, Friedhard Römer, Bernd Witzigmann, Tilman Schimpke, Martin Strassburg, Andrey Bakin, Hans Schumacher, Erwin Peiner, Hutomo Suryo Wasisto, Andreas Waag
Vertically aligned GaN nanowire (NW) arrays have attracted a lot of attention because of their potential for novel devices in the fields of optoelectronics and nanoelectronics. In this work, GaN NW arrays have been designed and fabricated by combining suitable nanomachining processes including dry and wet etching. After inductively coupled plasma (ICP) dry reactive ion etching (RIE), the GaN NWs are subsequently treated in wet chemical etching using AZ400K developer (i.e., with an activation energy of 0.69 �� 0...
January 9, 2017: Nanotechnology
Dawid Warszycki, Manuel Rueda, Stefan Mordalski, Kurt Kristiansen, Grzegorz Satała, Krzysztof Rataj, Zdzisław Chilmonczyk, Ingebrigt Sylte, Ruben Abagyan, Andrzej J Bojarski
Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to the X-ray crystallography community. This lack of direct structural information not only hampers our knowledge regarding the binding modes of many popular ligands (including the endogenous neurotransmitter-serotonin), but also limits the search for more potent compounds. In this paper we shed new light on the 3D pharmacological properties of the 5-HT1A receptor by using a ligand-guided approach (ALiBERO) grounded in the Internal Coordinate Mechanics (ICM) docking platform...
January 18, 2017: Journal of Chemical Information and Modeling
Yuriy V Zatsikha, Cole D Holstrom, Kullapa Chanawanno, Allen J Osinski, Christopher J Ziegler, Victor N Nemykin
The 1,3,7,9-tetraferrocenylazadipyrromethene (3) and the corresponding 1,3,5,7-tetraferrocene aza-BODIPY (4) were prepared via three and four synthetic steps, respectively, starting from ferrocenecarbaldehyde using the chalcone-type synthetic methodology. The novel tetra-iron compounds have ferrocene groups directly attached to both the α- and the β-pyrrolic positions, and the shortest Fe-Fe distance determined by X-ray crystallography for 3 was found to be ∼6.98 Å. These new compounds were characterized by UV-vis, nuclear magnetic resonance, and high-resolution electrospray ionization mass spectrometry methods, while metal-metal couplings in these systems were probed by electro- and spectroelectrochemistry, chemical oxidations, and Mössbauer spectroscopy...
January 5, 2017: Inorganic Chemistry
Jose M Arencibia, Wolfgang Fröhner, Magdalena Krupa, Daniel Pastor-Flores, Piotr Merker, Thomas Oellerich, Sonja Neimanis, Christian Schmithals, Verena Köberle, Evelyn Süß, Stefan Zeuzem, Holger Stark, Albrecht Piiper, Dalibor Odadzic, Jörg O Schulze, Ricardo M Biondi
There is a current and pressing need for improved cancer therapies. The use of small molecule kinase inhibitors and their application in combinatorial regimens represent an approach to personalized targeted cancer therapy. A number of AGC kinases, including atypical Protein Kinase C enzymes (PKCs), are validated drug targets for cancer treatment. Most drug development programs for protein kinases focus on the development of drugs that bind at the ATP-binding site. Alternatively, allosteric drugs have great potential for the development of future innovative drugs...
January 13, 2017: ACS Chemical Biology
Anthony J Metrano, Nadia C Abascal, Brandon Q Mercado, Eric K Paulson, Anna E Hurtley, Scott J Miller
X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced...
January 11, 2017: Journal of the American Chemical Society
Cynthia K Holland, Barbara Cascella, Joseph M Jez
In this issue of Cell Chemical Biology, Mori et al. (2016) combine X-ray crystallography and biochemistry to discover a new mechanism for stilbene synthesis in bacteria. The dialkyl-condensing enzyme StlD catalyzes formation of cyclohexanediones using a non-canonical β-ketosynthase active site. Aromatization by StlC completes production of the stilbene product.
December 22, 2016: Cell Chemical Biology
Ivan Polsinelli, Martin Savko, Cecile Rouanet-Mehouas, Lidia Ciccone, Susanna Nencetti, Elisabetta Orlandini, Enrico A Stura, William Shepard
X-ray radiation in macromolecular crystallography can chemically alter the biological material and deteriorate the integrity of the crystal lattice with concomitant loss of resolution. Typical alterations include decarboxylation of glutamic and aspartic residues, breaking of disulfide bonds and the reduction of metal centres. Helical scans add a small translation to the crystal in the rotation method, so that for every image the crystal is shifted to expose a fresh part. On beamline PROXIMA 2A at Synchrotron SOLEIL, this procedure has been tested with various parameters in an attempt to understand how to mitigate the effects of radiation damage...
January 1, 2017: Journal of Synchrotron Radiation
Matthew D Cheeseman, Nicola E A Chessum, Carl S Rye, A Elisa Pasqua, Michael J Tucker, Birgit Wilding, Lindsay E Evans, Susan Lepri, Meirion Richards, Swee Y Sharp, Salyha Ali, Martin Rowlands, Lisa O'Fee, Asadh Miah, Angela Hayes, Alan T Henley, Marissa Powers, Robert Te Poele, Emmanuel De Billy, Loredana Pellegrino, Florence Raynaud, Rosemary Burke, Rob L M van Montfort, Suzanne A Eccles, Paul Workman, Keith Jones
Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model...
December 22, 2016: Journal of Medicinal Chemistry
Matthew Fritz, Caitlin M Quinn, Mingzhang Wang, Guangjin Hou, Xingyu Lu, Leonardus M I Koharudin, Tatyana Polenova, Angela M Gronenborn
NMR chemical shifts are exquisitely sensitive probes for conformation and dynamics in molecules and supramolecular assemblies. Although isotropic chemical shifts are easily measured with high accuracy and precision in conventional NMR experiments, they remain challenging to calculate quantum mechanically, particularly in inherently dynamic biological systems. Using a model benchmark protein, the 133-residue agglutinin from Oscillatoria agardhii (OAA), which has been extensively characterized by us previously, we have explored the integration of X-ray crystallography, solution NMR, MAS NMR, and quantum mechanics/molecular mechanics (QM/MM) calculations for analysis of (13)C(α) and (15)N(H) isotropic chemical shifts...
December 21, 2016: Journal of Physical Chemistry. B
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