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Vincent Frappier, Justin M Jenson, Jianfu Zhou, Gevorg Grigoryan, Amy E Keating
Understanding the relationship between protein sequence and structure well enough to design new proteins with desired functions is a longstanding goal in protein science. Here, we show that recurring tertiary structural motifs (TERMs) in the PDB provide rich information for protein-peptide interaction prediction and design. TERM statistics can be used to predict peptide binding energies for Bcl-2 family proteins as accurately as widely used structure-based tools. Furthermore, design using TERM energies (dTERMen) rapidly and reliably generates high-affinity peptide binders of anti-apoptotic proteins Bfl-1 and Mcl-1 with just 15%-38% sequence identity to any known native Bcl-2 family protein ligand...
February 12, 2019: Structure
Yunpeng Shen, Damiaan E H F Mevius, Rocco Caliandro, Benedetta Carrozzini, Yeonjeong Roh, Jihyeon Kim, Sunghwan Kim, Sung Chul Ha, Masayo Morishita, Eric di Luccio
Histone methylation by histone methyltransferases (HMTases) has a key role in transcriptional regulation. Discrepancies between the known HMTases and the histone lysine methylome suggest that HMTases remain to be identified. Here we report the discovery, characterization, and crystal structure of Schizosaccharomyces pombe Set7, an HMTase methylating the uncharted histone H3 lysine 37 (H3K37) mark. Set7 forms a dimer with its substrate-binding site structurally specific to K37, not the neighboring well-studied K36 mark...
February 12, 2019: Structure
Hong Cheng, Vered Schwell, Brett R Curtis, Ruzaliya Fazlieva, Heinrich Roder, Kerry S Campbell
KIR3DL1 is an inhibitory killer cell immunoglobulin-like receptor (KIR) that negatively regulates natural killer cell cytotoxicity. The KIR3DL1 cytoplasmic region (3DL1-cyto) is disordered and can be dissected into three segments: (I) H340-V351; (II) M352-D371; and (III) P372-P423. NMR studies indicate that segment II can dynamically adopt a loop-like conformation, and segments I and III can form dynamic helices that may mediate binding to membranes, particularly in the region around the N-terminal (N) immunoreceptor tyrosine-based inhibitory motif (ITIM), consistent with its role in signaling...
February 6, 2019: Structure
Stéphanie Petrella, Estelle Capton, Bertrand Raynal, Clément Giffard, Aurélien Thureau, Françoise Bonneté, Pedro M Alzari, Alexandra Aubry, Claudine Mayer
Despite sharing common features, previous studies have shown that gyrases from different species have been modified throughout evolution to modulate their properties. Here, we report two crystal structures of Mycobacterium tuberculosis DNA gyrase, an apo and AMPPNP-bound form at 2.6-Å and 3.3-Å resolution, respectively. These structures provide high-resolution structural data on the quaternary organization and interdomain connections of a gyrase (full-length GyrB-GyrA57)2 thus providing crucial inputs on this essential drug target...
February 4, 2019: Structure
Min Xu, Jitin Singla, Elitza I Tocheva, Yi-Wei Chang, Raymond C Stevens, Grant J Jensen, Frank Alber
Electron cryotomography enables 3D visualization of cells in a near-native state at molecular resolution. The produced cellular tomograms contain detailed information about a plethora of macromolecular complexes, their structures, abundances, and specific spatial locations in the cell. However, extracting this information in a systematic way is very challenging, and current methods usually rely on individual templates of known structures. Here, we propose a framework called "Multi-Pattern Pursuit" for de novo discovery of different complexes from highly heterogeneous sets of particles extracted from entire cellular tomograms without using information of known structures...
January 31, 2019: Structure
Shoshana J Wodak, Emanuele Paci, Nikolay V Dokholyan, Igor N Berezovsky, Amnon Horovitz, Jing Li, Vincent J Hilser, Ivet Bahar, John Karanicolas, Gerhard Stock, Peter Hamm, Roland H Stote, Jerome Eberhardt, Yassmine Chebaro, Annick Dejaegere, Marco Cecchini, Jean-Pierre Changeux, Peter G Bolhuis, Jocelyne Vreede, Pietro Faccioli, Simone Orioli, Riccardo Ravasio, Le Yan, Carolina Brito, Matthieu Wyart, Paraskevi Gkeka, Ivan Rivalta, Giulia Palermo, J Andrew McCammon, Joanna Panecka-Hofman, Rebecca C Wade, Antonella Di Pizio, Masha Y Niv, Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang, Dzmitry Padhorny, Dima Kozakov, Tom McLeish
Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems...
January 17, 2019: Structure
Joan Teyra, Alex U Singer, Frank W Schmitges, Patrick Jaynes, Sarah Kit Leng Lui, Maria J Polyak, Nassima Fodil, Jonathan R Krieger, Jiefei Tong, Carsten Schwerdtfeger, Bradley B Brasher, Derek F J Ceccarelli, Jason Moffat, Frank Sicheri, Michael F Moran, Philippe Gros, Pieter J A Eichhorn, Martin Lenter, Guido Boehmelt, Sachdev S Sidhu
The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway...
January 17, 2019: Structure
Alister T Boags, Firdaus Samsudin, Syma Khalid
We present a molecular modeling and simulation study of the E. coli cell envelope, with a particular focus on the role of TolR, a native protein of the E. coli inner membrane, in interactions with the cell wall. TolR has been proposed to bind to peptidoglycan, but the only structure of this protein thus far is in a conformation in which the putative peptidoglycan binding domain is not accessible. We show that a model of the extended conformation of the protein in which this domain is exposed binds peptidoglycan largely through electrostatic interactions...
January 17, 2019: Structure
Sangbae Lee, Anita K Nivedha, Christopher G Tate, Nagarajan Vaidehi
Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of A2A R in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A2A receptor, we observed that the agonists show decreased ligand mobility, lower entropy of the extracellular loops in the active-intermediate state compared with the inactive state...
January 2, 2019: Structure
Kamal Kant Sharma, Xin-Xiang Lim, Sarala Neomi Tantirimudalige, Anjali Gupta, Jan K Marzinek, Daniel Holdbrook, Xin Ying Elisa Lim, Peter J Bond, Ganesh S Anand, Thorsten Wohland
Dengue is a mosquito-borne virus with dire health and economic impacts. Dengue is responsible for an estimated 390 million infections per year, with dengue 2 (DENV2) being the most virulent strain among the four serotypes. Interestingly, it is also in strains of this serotype that temperature-dependent large-scale morphological changes, termed "breathing," have been observed. Although the structure of these morphologies has been solved to 3.5-Å resolution, the dynamics of the viral envelope are unknown...
January 2, 2019: Structure
Brian Joseph Bender, Gerrit Vortmeier, Stefan Ernicke, Mathias Bosse, Anette Kaiser, Sylvia Els-Heindl, Ulrike Krug, Annette Beck-Sickinger, Jens Meiler, Daniel Huster
The peptide ghrelin targets the growth hormone secretagogue receptor 1a (GHSR) to signal changes in cell metabolism and is a sought-after therapeutic target, although no structure is known to date. To investigate the structural basis of ghrelin binding to GHSR, we used solid-state nuclear magnetic resonance (NMR) spectroscopy, site-directed mutagenesis, and Rosetta modeling. The use of saturation transfer difference NMR identified key residues in the peptide for receptor binding beyond the known motif. This information combined with assignment of the secondary structure of ghrelin in its receptor-bound state was incorporated into Rosetta using an approach that accounts for flexible binding partners...
December 28, 2018: Structure
Michael W Martynowycz, Wei Zhao, Johan Hattne, Grant J Jensen, Tamir Gonen
Microcrystal electron diffraction (MicroED) allows for macromolecular structure solution from nanocrystals. To create crystals of suitable size for MicroED data collection, sample preparation typically involves sonication or pipetting a slurry of crystals from a crystallization drop. The resultant crystal fragments are fragile and the quality of the data that can be obtained from them is sensitive to subsequent sample preparation for cryoelectron microscopy as interactions in the water-air interface can damage crystals during blotting...
December 28, 2018: Structure
Saurabh Shukla, Chuankai Zhao, Diwakar Shukla
Plant hormones are essential mediators of plant responses to environmental stresses. Abscisic acid (ABA) is a hormone that helps plants survive drought by mediating guard cell closure. Since the identification of PYR/PYL/RCAR ABA receptors, the mechanism underlying ABA signaling has been intensely investigated. However, dynamic and energetic aspects of ABA-mediated activation of receptors and their downregulation by post-translational modifications remain elusive. Using molecular simulations, we establish complete ABA recognition pathways by two subtype receptors (PYL5 and PYL10) and a modified PYL5 receptor through tyrosine nitration...
December 19, 2018: Structure
Inessa De, Emily C Chittock, Helga Grötsch, Thomas C R Miller, Andrew A McCarthy, Christoph W Müller
Ubiquitin C-terminal hydrolase deubiquitinase BAP1 is an essential tumor suppressor involved in cell growth control, DNA damage response, and transcriptional regulation. As part of the Polycomb repression machinery, BAP1 is activated by the deubiquitinase adaptor domain of ASXL1 mediating gene repression by cleaving ubiquitin (Ub) from histone H2A in nucleosomes. The molecular mechanism of BAP1 activation by ASXL1 remains elusive, as no structures are available for either BAP1 or ASXL1. Here, we present the crystal structure of the BAP1 ortholog from Drosophila melanogaster, named Calypso, bound to its activator, ASX, homolog of ASXL1...
December 18, 2018: Structure
Wen Li, Rajendra K Agrawal
With recent technological advancements, single-particle cryogenic electron microscopy (cryo-EM) is now the technique of choice to study structure and function of biological macromolecules at near-atomic resolution. Many single-particle EM reconstruction methods necessary for these advances were pioneered by Joachim Frank, and were optimized using the ribosome as a benchmark specimen. In doing so, he made several landmark contributions to the understanding of the structure and function of ribosomes. These include the first 3D visualization of ribosome-bound transfer RNAs, the first experimentally derived structures of the primary complexes formed during the bacterial translation elongation cycle, and the critical ribosomal conformational transitions required for translation...
December 18, 2018: Structure
Valérie Campanacci, Agathe Urvoas, Tanja Consolati, Soraya Cantos-Fernandes, Magali Aumont-Nicaise, Marie Valerio-Lepiniec, Thomas Surrey, Philippe Minard, Benoît Gigant
Microtubules are cytoskeletal filaments of eukaryotic cells made of αβ-tubulin heterodimers. Structural studies of non-microtubular tubulin rely mainly on molecules that prevent its self-assembly and are used as crystallization chaperones. Here we identified artificial proteins from an αRep library that are specific to α-tubulin. Turbidity experiments indicate that these αReps impede microtubule assembly in a dose-dependent manner and total internal reflection fluorescence microscopy further shows that they specifically block growth at the microtubule (-) end...
December 17, 2018: Structure
Ewald Heroes, Gerd Van der Hoeven, Meng S Choy, Javier Del Pino Garcia, Mónica Ferreira, Mieke Nys, Rita Derua, Monique Beullens, Chris Ulens, Wolfgang Peti, Luc Van Meervelt, Rebecca Page, Mathieu Bollen
SDS22 is an ancient regulator of protein phosphatase-1 (PP1). Our crystal structure of SDS22 shows that its twelve leucine-rich repeats adopt a banana-shaped fold that is shielded from solvent by capping domains at its extremities. Subsequent modeling and biochemical studies revealed that the concave side of SDS22 likely interacts with PP1 helices α5 and α6, which are distal from the binding sites of many previously described PP1 interactors. Accordingly, we found that SDS22 acts as a "third" subunit of multiple PP1 holoenzymes...
December 17, 2018: Structure
Robert E London
There has been a steadily increasing appreciation of the fact that the relationship between protein sequence and structure is often sufficiently ambiguous to allow a single sequence to adopt alternative, stable folds. Living organisms have been able to utilize such metamorphic proteins in remarkable and unanticipated ways. HIV-1 reverse transcriptase is among the earliest such proteins identified and remains a unique example in which a functional heterodimer contains two, alternatively folded polymerase domains...
December 17, 2018: Structure
Yi Peng, Shufen Cao, Janna Kiselar, Xiangzhu Xiao, Zhanwen Du, An Hsieh, Soobin Ko, Yinghua Chen, Prashansa Agrawal, Wenwei Zheng, Wuxian Shi, Wei Jiang, Lin Yang, Mark R Chance, Witold K Surewicz, Matthias Buck, Sichun Yang
The N-terminal transactivation domain (NTD) of estrogen receptor alpha, a well-known member of the family of intrinsically disordered proteins, mediates the receptor's transactivation function. However, an accurate molecular dissection of NTD's structure-function relationships remains elusive. Here, we show that the NTD adopts a mostly disordered, unexpectedly compact conformation that undergoes structural expansion on chemical denaturation. By combining small-angle X-ray scattering, hydroxyl radical protein footprinting, and computational modeling, we derive the ensemble-structures of the NTD and determine its ensemble-contact map revealing metastable long-range contacts, e...
December 13, 2018: Structure
Satomi Kori, Laure Ferry, Shohei Matano, Tomohiro Jimenji, Noriyuki Kodera, Takeshi Tsusaka, Rumie Matsumura, Takashi Oda, Mamoru Sato, Naoshi Dohmae, Toshio Ando, Yoichi Shinkai, Pierre-Antoine Defossez, Kyohei Arita
The protein UHRF1 is crucial for DNA methylation maintenance. The tandem Tudor domain (TTD) of UHRF1 binds histone H3K9me2/3 with micromolar affinity, as well as unmethylated linker regions within UHRF1 itself, causing auto-inhibition. Recently, we showed that a methylated histone-like region of DNA ligase 1 (LIG1K126me2/me3) binds the UHRF1 TTD with nanomolar affinity, permitting UHRF1 recruitment to chromatin. Here we report the crystal structure of the UHRF1 TTD bound to a LIG1K126me3 peptide. The data explain the basis for the high TTD-binding affinity of LIG1K126me3 and reveal that the interaction may be regulated by phosphorylation...
December 12, 2018: Structure
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