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X-ray crystallography

David M Thal, Ziva Vuckovic, Christopher J Draper-Joyce, Yi-Lynn Liang, Alisa Glukhova, Arthur Christopoulos, Patrick M Sexton
G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface receptor proteins and are important drug targets for many human diseases. In the last decade, remarkable progress has been made in the determination of atomic structures of GPCRs with over 200 structures from 53 unique receptors having been solved. Technological advances in protein engineering and X-ray crystallography have driven much of the progress to date. However, recent advances in cryo-electron microscopy have facilitated the structural determination of three new structures of active-state GPCRs in complex with heterotrimeric G protein...
March 13, 2018: Current Opinion in Structural Biology
Ana Trapero, Angela Pacitto, Vinayak Singh, Mohamad Sabbah, Anthony G Coyne, Valerie Mizrahi, Tom L Blundell, David B Ascher, Chris Abell
Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5´-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible (Mth) IMPDH(ΔCBS) inhibitors identified a low affinity phenylimidazole derivative...
March 16, 2018: Journal of Medicinal Chemistry
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
Paween Mahinthichaichan, Robert B Gennis, Emad Tajkhorshid
Cytochrome aa3 is the terminal respiratory enzyme of all eukaryotes and many bacteria and archaea, reducing O2 to water and harnessing the free energy from the reaction to generate the transmembrane electrochemical potential. The diffusion of O2 to the heme-copper catalytic site, which is buried deep inside the enzyme, is the initiation step of the reaction chemistry. Our previous molecular dynamics (MD) study with cytochrome ba3 , a homologous enzyme of cytochrome aa3 in Thermus thermophilus, demonstrated that O2 diffuses from the lipid bilayer to its reduction site through a 25-Å long tunnel inferred by Xe-binding sites detected by X-ray crystallography$ ...
March 16, 2018: Biochemistry
G K Selikhanov, M S Fando, M V Dontsova, A G Gabdulkhakov
This review contains recent data on serial femtosecond X-ray crystallography (SFX), based on a femtosecond X-ray free electron laser, as well as, on the possibilities of its application for studying photosensitive proteins. Development of this method began rather recently, and it has already shown its effectiveness and some unique advantages over conventional X-ray structural analysis. This technology is especially promising for structural studies of membrane proteins and for kinetic studies. The main principle of the method, the possibility of its application in structural biology, its advantages and disadvantages, as well as its prospects for further development are analyzed in this review...
January 2018: Biochemistry. Biokhimii︠a︡
Anushka C Galasiti Kankanamalage, Yunjeong Kim, Vishnu C Damalanka, Athri D Rathnayake, Anthony R Fehr, Nurjahan Mehzabeen, Kevin P Battaile, Scott Lovell, Gerald H Lushington, Stanley Perlman, Kyeong-Ok Chang, William C Groutas
There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties...
March 6, 2018: European Journal of Medicinal Chemistry
Benjamin Stauch, Vadim Cherezov
G protein-coupled receptors (GPCRs) represent a large superfamily of membrane proteins that mediate cell signaling and regulate a variety of physiological processes in the human body. Structure-function studies of this superfamily were enabled a decade ago by multiple breakthroughs in technology that included receptor stabilization, crystallization in a membrane environment, and microcrystallography. The recent emergence of X-ray free-electron lasers (XFELs) has further accelerated structural studies of GPCRs and other challenging proteins by overcoming radiation damage and providing access to high-resolution structures and dynamics using micrometer-sized crystals...
March 15, 2018: Annual Review of Biophysics
Artur Lik, Sangeth Jenthra, Lars Fritze, Lars Müller, Khai-Nghi Truong, Holger Helten
The application of our newly developed B-C coupling method by catalytic Si/B exchange is demonstrated for the synthesis of a series of triarylboranes (1), monodisperse thienyl- and furylborane dimers (2) and trimers (9), extended oligomers (3) and polymers (3'), as well as mixed (oligo)thienyl-/furylboranes. The structures of 1aaTip, 1bbTip, and 2bbbMes*, determined by X-ray crystallography, reveal largely coplanar hetarene rings and BR3 environments, being most pronounced in the furylborane species. Photophysical investigations, supported by TD-DFT calculations, revealed pronounced pi-electron delocalization over the hetarene backbones including the boron centers...
March 15, 2018: Chemistry: a European Journal
Verity A Jackson, Dimphna H Meijer, Maria Carrasquero, Laura S van Bezouwen, Edward D Lowe, Colin Kleanthous, Bert J C Janssen, Elena Seiradake
Teneurins are ancient cell-cell adhesion receptors that are vital for brain development and synapse organisation. They originated in early metazoan evolution through a horizontal gene transfer event when a bacterial YD-repeat toxin fused to a eukaryotic receptor. We present X-ray crystallography and cryo-EM structures of two Teneurins, revealing a ~200 kDa extracellular super-fold in which eight sub-domains form an intricate structure centred on a spiralling YD-repeat shell. An alternatively spliced loop, which is implicated in homophilic Teneurin interaction and specificity, is exposed and thus poised for interaction...
March 14, 2018: Nature Communications
Liang Zhang, David August, Jiankang Zhong, George F S Whitehead, Inigo J Vitorica-Yrezabal, David A Leigh
We report the two-step synthesis of a molecular trefoil knot in 90 % overall yield through the self-assembly of a twelve-component trimeric circular zinc helicate followed by ring closing metathesis of six pendant alkene chains. Both the trimeric circular helicate intermediate and the resulting trefoil knot were characterized by NMR spectroscopy, mass spectrometry and X-ray crystallography.
March 14, 2018: Journal of the American Chemical Society
J Vincent Edwards, Krystal Fontenot, Falk Liebner, Nicole Doyle Nee Pircher, Alfred D French, Brian D Condon
Nanocellulose has high specific surface area, hydration properties, and ease of derivatization to prepare protease sensors. A Human Neutrophil Elastase sensor designed with a nanocellulose aerogel transducer surface derived from cotton is compared with cotton filter paper, and nanocrystalline cellulose versions of the sensor. X-ray crystallography was employed along with Michaelis-Menten enzyme kinetics, and circular dichroism to contrast the structure/function relations of the peptide-cellulose conjugate conformation to enzyme/substrate binding and turnover rates...
March 13, 2018: International Journal of Molecular Sciences
Kuppuswamy Arumugam, Malathy Selvachandran, Antony Obanda, Mohamed C Shaw, Perumalreddy Chandrasekaran, Sonya L Caston Good, Joel T Mague, Stephen Sproules, James P Donahue
Compounds of the type [(S2 C2 R2 )M(μ-tpbz)M(S2 C2 R2 )] (R = CN, Me, Ph, p-anisyl; M = Ni, Pd, Pt; tpbz = 1,2,4,5-tetrakis(diphenylphosphino)benzene) have been prepared by transmetalation with [(S2 C2 R2 )SnR'2 ] reagents, by direct displacement of dithiolene ligand from [M(S2 C2 R2 )2 ] with 0.5 equiv of tpbz, or by salt metathesis using Na2 [S2 C2 (CN)2 ] in conjunction with X2 M(μ-tpbz)MX2 (X = halide). X-ray crystallography reveals a range of topologies (undulating, chair, bowed) for the (S2 C2 )M(P2 C6 P2 )M(S2 C2 ) core...
March 13, 2018: Inorganic Chemistry
Jonathan M Grimes, David R Hall, Alun W Ashton, Gwyndaf Evans, Robin L Owen, Armin Wagner, Katherine E McAuley, Frank von Delft, Allen M Orville, Thomas Sorensen, Martin A Walsh, Helen M Ginn, David I Stuart
Macromolecular crystallography (MX) has been a motor for biology for over half a century and this continues apace. A series of revolutions, including the production of recombinant proteins and cryo-crystallography, have meant that MX has repeatedly reinvented itself to dramatically increase its reach. Over the last 30 years synchrotron radiation has nucleated a succession of advances, ranging from detectors to optics and automation. These advances, in turn, open up opportunities. For instance, a further order of magnitude could perhaps be gained in signal to noise for general synchrotron experiments...
February 1, 2018: Acta Crystallographica. Section D, Structural Biology
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
Liz Potterton, Jon Agirre, Charles Ballard, Kevin Cowtan, Eleanor Dodson, Phil R Evans, Huw T Jenkins, Ronan Keegan, Eugene Krissinel, Kyle Stevenson, Andrey Lebedev, Stuart J McNicholas, Robert A Nicholls, Martin Noble, Navraj S Pannu, Christian Roth, George Sheldrick, Pavol Skubak, Johan Turkenburg, Ville Uski, Frank von Delft, David Waterman, Keith Wilson, Martyn Winn, Marcin Wojdyr
The CCP4 (Collaborative Computational Project, Number 4) software suite for macromolecular structure determination by X-ray crystallography groups brings together many programs and libraries that, by means of well established conventions, interoperate effectively without adhering to strict design guidelines. Because of this inherent flexibility, users are often presented with diverse, even divergent, choices for solving every type of problem. Recently, CCP4 introduced CCP4i2, a modern graphical interface designed to help structural biologists to navigate the process of structure determination, with an emphasis on pipelining and the streamlined presentation of results...
February 1, 2018: Acta Crystallographica. Section D, Structural Biology
Oliver S Smart, Vladimír Horský, Swanand Gore, Radka Svobodová Vařeková, Veronika Bendová, Gerard J Kleywegt, Sameer Velankar
Realising the importance of assessing the quality of the biomolecular structures deposited in the Protein Data Bank (PDB), the Worldwide Protein Data Bank (wwPDB) partners established Validation Task Forces to obtain advice on the methods and standards to be used to validate structures determined by X-ray crystallography, nuclear magnetic resonance spectroscopy and three-dimensional electron cryo-microscopy. The resulting wwPDB validation pipeline is an integral part of the wwPDB OneDep deposition, biocuration and validation system...
March 1, 2018: Acta Crystallographica. Section D, Structural Biology
Oliver S Smart, Vladimír Horský, Swanand Gore, Radka Svobodová Vařeková, Veronika Bendová, Gerard J Kleywegt, Sameer Velankar
Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) play a crucial role in structure-guided drug discovery and design, and also provide atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. The quality with which small-molecule ligands have been modelled in Protein Data Bank (PDB) entries has been, and continues to be, a matter of concern for many investigators. Correctly interpreting whether electron density found in a binding site is compatible with the soaked or co-crystallized ligand or represents water or buffer molecules is often far from trivial...
March 1, 2018: Acta Crystallographica. Section D, Structural Biology
Ronan M Keegan, Stuart J McNicholas, Jens M H Thomas, Adam J Simpkin, Felix Simkovic, Ville Uski, Charles C Ballard, Martyn D Winn, Keith S Wilson, Daniel J Rigden
Increasing sophistication in molecular-replacement (MR) software and the rapid expansion of the PDB in recent years have allowed the technique to become the dominant method for determining the phases of a target structure in macromolecular X-ray crystallography. In addition, improvements in bioinformatic techniques for finding suitable homologous structures for use as MR search models, combined with developments in refinement and model-building techniques, have pushed the applicability of MR to lower sequence identities and made weak MR solutions more amenable to refinement and improvement...
March 1, 2018: Acta Crystallographica. Section D, Structural Biology
Cecilia Augustsson, Anders Svensson, Birgitte Kjaer, Tzu-Yuan Chao, Xia Wenjuan, Berit Olsen Krogh, Jens Breinholt, Jes Thorn Clausen, Ida Hilden, Helle Heibroch Petersen, Lars Christian Petersen
BACKGROUND: Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI). TFPI contains three Kunitz-type protease inhibitor domains (K1-K3) of which K1 and K2 block the active sites of FVIIa and FXa respectively. OBJECTIVE: To produce a monoclonal antibody (mAb) directed towards K1, to characterize the binding epitope, and to study its effect on TFPI inhibition...
March 12, 2018: Journal of Thrombosis and Haemostasis: JTH
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
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