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Chemical crystallography

Stephanie Heinzlmeir, Jonas Lohse, Tobias Treiber, Denis Kudlinzki, Verena Linhard, Santosh Lakshmi Gande, Sridhar Sreeramulu, Krishna Saxena, Xiaofeng Liu, Mathias Wilhelm, Harald Schwalbe, Bernhard Kuster, Guillaume Médard
The receptor tyrosine kinase EPHA2 has gained interest as therapeutic drug target in cancer and infectious diseases. However, EPHA2 research and EPHA2-based therapies have been hampered by the lack of selective small molecule inhibitors. Here, we report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as a lead structure. We designed hybrid structures of Dasatinib and the previously known EPHA2 binders CHEMBL249097, PD-173955 and a known EPHB4 inhibitor in order to exploit both the ATP pocket entrance as well as the ribose pocket as binding epitopes in the kinase EPHA2...
May 24, 2017: ChemMedChem
Ya-Long Zhang, Xu-Wei Zhou, Xiao-Bing Wang, Lin Wu, Ming-Hua Yang, Jun Luo, Yong Yin, Jian-Guang Luo, Ling-Yi Kong
Xylopiana A (1), a dimeric guaiane with an unprecedented pentacyclo[,2).0(4,5').0(5,4')]decane-3,2'-dione core, and three biosynthetically related intermediates, compounds 2-4, were isolated from the leaves of Xylopia vielana. Their structures and absolute configurations were determined by a combination of spectroscopic data, X-ray crystallography, electronic circular dichroism calculations, and chemical conversion. The structure of known vielanin A was revised to be compound 3. Compound 4 exerted a 3...
May 24, 2017: Organic Letters
Ira V Rozhdestvenskaya, Enrico Mugnaioli, Marco Schowalter, Martin U Schmidt, Michael Czank, Wulf Depmeier, Andreas Rosenauer
Denisovite is a rare mineral occurring as aggregates of fibres typically 200-500 nm diameter. It was confirmed as a new mineral in 1984, but important facts about its chemical formula, lattice parameters, symmetry and structure have remained incompletely known since then. Recently obtained results from studies using microprobe analysis, X-ray powder diffraction (XRPD), electron crystallography, modelling and Rietveld refinement will be reported. The electron crystallography methods include transmission electron microscopy (TEM), selected-area electron diffraction (SAED), high-angle annular dark-field imaging (HAADF), high-resolution transmission electron microscopy (HRTEM), precession electron diffraction (PED) and electron diffraction tomography (EDT)...
May 1, 2017: IUCrJ
Emiliano Tamanini, Ildiko Maria Buck, Gianni Chessari, Elisabetta Chiarparin, James E H Day, Martyn Frederickson, Charlotte M Griffiths-Jones, Keisha Hearn, Tom D Heightman, Aman Iqbal, Christopher Norbert Johnson, Edward J Lewis, Vanessa Martins, Torren Peakman, Michael Reader, Sharna J Rich, George A Ward, Pamela A Williams, Nicola E Wilsher
XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology...
May 11, 2017: Journal of Medicinal Chemistry
Tamsyn Hilder, Justin Hodgkiss
DNA aptamers can exhibit high affinity and selectivity towards their targets, but the aptamer-target complex structures are rarely available from crystallography and often difficult to elucidate. This is particularly true of small molecule targets, including 17β-estradiol (E2), which is becoming one of the most widely encountered endocrine-disrupting chemicals in the environment. Using molecular dynamics simulations, we demonstrate that E2 binds to a thymine loop region common to all E2-specific aptamers in the literature...
May 7, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
Volker L Deringer, Janine George, Richard Dronskowski, Ulli Englert
Molecular compounds, organic and inorganic, crystallize in diverse and complex structures. They continue to inspire synthetic efforts and "crystal engineering", with implications ranging from fundamental questions to pharmaceutical research. The structural complexity of molecular solids is linked with diverse intermolecular interactions: hydrogen bonding with all its facets, halogen bonding, and other secondary bonding mechanisms of recent interest (and debate). Today, high-resolution diffraction experiments allow unprecedented insight into the structures of molecular crystals...
May 3, 2017: Accounts of Chemical Research
Huijuan Guo, René Benndorf, Daniel Leichnitz, Jonathan L Klassen, John Vollmers, Helmar Görls, Matthias Steinacker, Christiane Weigel, Hans-Martin Dahse, Anne-Kristin Kaster, Z Wilhelm de Beer, Michael Poulsen, Christine Beemelmanns
We report the discovery of six new highly substituted tropolone alkaloids, rubterolones A-F, from Actinomadura sp. 5 2, isolated from the gut of the fungus-growing termite Macrotermes natalensis. Rubterolones were identified using fungus-bacteria challenge assays and a HRMS-based dereplication strategy, and characterized by NMR and HRMS analyses and X-ray crystallography. Feeding experiments and subsequent chemical derivatisation led to a first library of rubterolones derivatives (A-L). Genome sequencing and comparative analyses revealed their putative biosynthetic pathway, which was supported by feeding experiments...
May 2, 2017: Chemistry: a European Journal
James R Pankhurst, Nicola L Bell, Markus Zegke, Lucy N Platts, Carlos Alvarez Lamfsus, Laurent Maron, Louise S Natrajan, Stephen Sproules, Polly L Arnold, Jason B Love
The uranyl(vi) complex UO2Cl(L) of the redox-active, acyclic diimino-dipyrrin anion, L(-) is reported and its reaction with inner- and outer-sphere reductants studied. Voltammetric, EPR-spectroscopic and X-ray crystallographic studies show that chemical reduction by the outer-sphere reagent CoCp2 initially reduces the ligand to a dipyrrin radical, and imply that a second equivalent of CoCp2 reduces the U(vi) centre to form U(v). Cyclic voltammetry indicates that further outer-sphere reduction to form the putative U(iv) trianion only occurs at strongly cathodic potentials...
January 1, 2017: Chemical Science
Artur J Moro, A Jorge Parola, Fernando Pina, Ana-Maria Pana, Valentin Badea, Iulia Pausescu, Sergiu Shova, Liliana Cseh
The chemistry of 2,2'-spirobis[chromene] derivatives is intimately related to the one of anthocyanins and similar compounds. The 2,2'-spirobis[chromene] species plays a central role in the network of chemical reactions connecting two different flavylium-based multistate systems. In the present work, a new asymmetric 2,2'-spirobis[chromene] intermediate possessing a constrained propylenic bridge between carbons 3 and 3' was isolated and its role as a pivot in the anthocyanins-type multistate of chemical reactions was investigated by the conjugation of absorption spectroscopy, stopped-flow, NMR, and X-ray crystallography...
May 4, 2017: Journal of Organic Chemistry
Guo-Yong Luo, Rui Deng, Jing-Jie Zhang, Jiang-Hai Ye, Lu-Tai Pan
The present study was performed to investigate the chemical components of the branches and leaves of Isodon rubescens. Two 6,7-seco-spiro-lacton-ent-kauranoids were obtained. Based on the extensive spectroscopic analyses, their structures were elucidated as 6-epi-11-O-acetylangustifolin (1) and 11-O-acetylangustifolin (2), respectively. The structure of 2 was further comfirmed by X-ray crystallography analysis. MTT method was employed to evaluate their cytotoxity against human lung cancer cell lines A549 and leukemia cell lines K562...
April 24, 2017: Journal of Asian Natural Products Research
M Altissimo, M Kiskinova, R Mincigrucci, L Vaccari, C Guarnaccia, C Masciovecchio
Revealing the structure of complex biological macromolecules, such as proteins, is an essential step for understanding the chemical mechanisms that determine the diversity of their functions. Synchrotron based X-ray crystallography and cryo-electron microscopy have made major contributions in determining thousands of protein structures even from micro-sized crystals. They suffer from some limitations that have not been overcome, such as radiation damage, the natural inability to crystallize a number of proteins, and experimental conditions for structure determination that are incompatible with the physiological environment...
July 2017: Structural Dynamics (Melville, N.Y.)
Yizhou Liu, Josep Saurí, Emily Mevers, Mark W Peczuh, Henk Hiemstra, Jon Clardy, Gary E Martin, R Thomas Williamson
Assignment of complex molecular structures from nuclear magnetic resonance (NMR) data can be prone to interpretational mistakes. Residual dipolar couplings and residual chemical shift anisotropy provide a spatial view of the relative orientations between bonds and chemical shielding tensors, respectively, regardless of separation. Consequently, these data constitute a reliable reporter of global structural validity. Anisotropic NMR parameters can be used to evaluate investigators' structure proposals or structures generated by computer-assisted structure elucidation...
April 7, 2017: Science
Md Munan Shaik, Nicholus Bhattacharjee, Mikolaj Feliks, Kenneth K-S Ng, Martin J Field
Norovirus (NV) RNA-dependent RNA polymerase (RdRP) is essential for replicating the genome of the virus, which makes this enzyme a key target for the development of antiviral agents against NV gastroenteritis. In this work, a complex of NV RdRP bound to manganese ions and an RNA primer-template duplex was investigated using X-ray crystallography and hybrid quantum chemical/molecular mechanical simulations. Experimentally, the complex crystallized in a tetragonal crystal form. The nature of the primer/template duplex binding in the resulting structure indicates that the complex is a closed back-tracked state of the enzyme, in which the 3'-end of the primer occupies the position expected for the post-incorporated nucleotide before translocation...
April 6, 2017: Proteins
Ali Ryan, Elena Polycarpou, Nathan A Lack, Dimitrios Evangelopoulos, Christian Sieg, Alice Halman, Sanjib Bhakta, Olga Eleftheriadou, Timothy D McHugh, Sebastian Keany, Edward D Lowe, Romain Ballet, Areej Abuhammad, William R Jacobs, Alessio Ciulli, Edith Sim
BACKGROUND AND PURPOSE: With the emergence of extensively drug-resistant tuberculosis, there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG. EXPERIMENTAL APPROACH: We generated a mutant strain of M...
April 5, 2017: British Journal of Pharmacology
Marissa A McKercher, Xiaoyang Guan, Zhongping Tan, Deborah S Wuttke
SH2 domains recognize phosphotyrosine (pY)-containing peptide ligands and play key roles in the regulation of receptor tyrosine kinase pathways. Each SH2 domain has individualized specificity, encoded in the amino acids neighboring the pY, for defined targets that convey their distinct functions. The C-terminal SH2 domain (PLCC) of the phospholipase C-γ1 full-length protein (PLCγ1) typically binds peptides containing small and hydrophobic amino acids adjacent to the pY, including a peptide derived from platelet-derived growth factor receptor B (PDGFRB) and an intraprotein recognition site (Y783 of PLCγ1) involved in the regulation of the protein's lipase activity...
April 25, 2017: Biochemistry
Hosung Ki, Key Young Oang, Jeongho Kim, Hyotcherl Ihee
Time-resolved X-ray diffraction provides direct information on three-dimensional structures of reacting molecules and thus can be used to elucidate structural dynamics of chemical and biological reactions. In this review, we discuss time-resolved X-ray diffraction on small molecules and proteins with particular emphasis on its application to crystalline (crystallography) and liquid-solution (liquidography) samples. Time-resolved X-ray diffraction has been used to study picosecond and slower dynamics at synchrotrons and can now access even femtosecond dynamics with the recent arrival of X-ray free-electron lasers...
May 5, 2017: Annual Review of Physical Chemistry
Manish B Shah, Jingbao Liu, Qinghai Zhang, C David Stout, James R Halpert
Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2...
May 19, 2017: ACS Chemical Biology
Abdulselam Adam, Gebhard Haberhauer, Christoph Wölper
Cyclic oligomers of azole peptides were isolated from a multitude of marine organisms and were used for a large number of molecular machines. As shown previously, oligomers derived from achiral imidazole amino acids fold into canonical helices. Here we show that a minor change, the introduction of a methyl group in the δ position, results in a significant change in the secondary structure of the corresponding oligomers. Instead of a canonical helix, a noncanonical herringbone helix is formed. In the latter, the slope along the helix changes its sign at least twice per turn...
April 12, 2017: Journal of Organic Chemistry
Pengzhi Zhang, Swarnendu Tripathi, Hoa Trinh, Margaret S Cheung
We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca(2+)) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca(2+)/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca(2+) signaling pathways in neurons. It was shown experimentally that Ca(2+)/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca(2+)-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca(2+) affinity for CaM...
March 28, 2017: Biophysical Journal
Rongchun Zhang, Kamal H Mroue, Ayyalusamy Ramamoorthy
Protons are vastly abundant in a wide range of exciting macromolecules and thus can be a powerful probe to investigate the structure and dynamics at atomic resolution using solid-state NMR (ssNMR) spectroscopy. Unfortunately, the high signal sensitivity, afforded by the high natural-abundance and high gyromagnetic ratio of protons, is greatly compromised by severe line broadening due to the very strong (1)H-(1)H dipolar couplings. As a result, protons are rarely used, in spite of the desperate need for enhancing the sensitivity of ssNMR to study a variety of systems that are not amenable for high resolution investigation using other techniques including X-ray crystallography, cryo-electron microscopy, and solution NMR spectroscopy...
March 29, 2017: Accounts of Chemical Research
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