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Daniel B Grabarczyk, Sabrina Silkenat, Caroline Kisker
Ctf18-RFC is an alternative PCNA loader which plays important but poorly understood roles in multiple DNA replication-associated processes. To fulfill its specialist roles, the Ctf18-RFC clamp loader contains a unique module in which the Dcc1-Ctf8 complex is bound to the C terminus of Ctf18 (the Ctf18-1-8 module). Here, we report the structural and functional characterization of the heterotetrameric complex formed between Ctf18-1-8 and a 63 kDa fragment of DNA polymerase ɛ. Our data reveal that Ctf18-1-8 binds stably to the polymerase and far from its other functional sites, suggesting that Ctf18-RFC could be associated with Pol ɛ throughout normal replication as the leading strand clamp loader...
December 6, 2017: Structure
Eva De Mol, Elzbieta Szulc, Claudio Di Sanza, Paula Martínez-Cristóbal, Carlos W Bertoncini, R Bryn Fenwick, Marta Frigolé-Vivas, Marianela Masín, Irene Hunter, Víctor Buzón, Isabelle Brun-Heath, Jesús García, Gianni De Fabritiis, Eva Estébanez-Perpiñá, Iain J McEwan, Ángel R Nebreda, Xavier Salvatella
The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF...
December 6, 2017: Structure
Zhenzheng Hu, Xiangyi Shi, Bowen Yu, Na Li, Ying Huang, Yongning He
Mannose receptor (MR, CD206) is an endocytic receptor on microphages and dendritic cells. It recognizes multiple ligands and plays important roles in regulating immune responses and maintaining glycoprotein homeostasis. However, the structure and functional mechanism of MR remain unclear. Here we determine the crystal structures of the N-terminal fragments of MR and reveal the potential binding mode of collagen on the fibronectin II domain. The SAXS and other biophysical data suggest that MR adopts an extended conformation at physiological pH and undergoes conformational changes as pH decreases, resulting in a compact conformation in an acidic environment...
December 6, 2017: Structure
Vito Genna, Matteo Colombo, Marco De Vivo, Marco Marcia
Synthesis and scission of phosphodiester bonds in DNA and RNA regulate vital processes within the cell. Enzymes that catalyze these reactions operate mostly via the recognized two-metal-ion mechanism. Our analysis reveals that basic amino acids and monovalent cations occupy structurally conserved positions nearby the active site of many two-metal-ion enzymes for which high-resolution (<3 Å) structures are known, including DNA and RNA polymerases, nucleases such as Cas9, and splicing ribozymes. Integrating multiple-sequence and structural alignments with molecular dynamics simulations, electrostatic potential maps, and mutational data, we found that these elements always interact with the substrates, suggesting that they may play an active role for catalysis, in addition to their electrostatic contribution...
December 1, 2017: Structure
Ryoji Suno, Kanako Terakado Kimura, Takanori Nakane, Keitaro Yamashita, Junmei Wang, Takaaki Fujiwara, Yasuaki Yamanaka, Dohyun Im, Shoichiro Horita, Hirokazu Tsujimoto, Maki S Tawaramoto, Takatsugu Hirokawa, Eriko Nango, Kensuke Tono, Takashi Kameshima, Takaki Hatsui, Yasumasa Joti, Makina Yabashi, Keiko Shimamoto, Masaki Yamamoto, Daniel M Rosenbaum, So Iwata, Tatsuro Shimamura, Takuya Kobayashi
Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-Å and 1.96-Å resolution. In comparison with the non-subtype-selective antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at the orthosteric site, explaining the faster dissociation rate...
November 27, 2017: Structure
Veronika Csizmok, Meri Montecchio, Hong Lin, Mike Tyers, Maria Sunnerhagen, Julie D Forman-Kay
Many regulatory proteins, including the transcription factor c-Jun, are highly enriched in disordered protein regions that govern growth, division, survival, differentiation, and response to signals. The stability of c-Jun is controlled by poorly understood regulatory interactions of its disordered region with both the E3 ubiquitin ligase SCFFbw7 and prolyl cis-trans isomerase Pin1. We use nuclear magnetic resonance and fluorescence studies of c-Jun to demonstrate that multisite c-Jun phosphorylation is required for high-affinity interaction with Fbw7...
November 27, 2017: Structure
Swanand Gore, Eduardo Sanz García, Pieter M S Hendrickx, Aleksandras Gutmanas, John D Westbrook, Huanwang Yang, Zukang Feng, Kumaran Baskaran, John M Berrisford, Brian P Hudson, Yasuyo Ikegawa, Naohiro Kobayashi, Catherine L Lawson, Steve Mading, Lora Mak, Abhik Mukhopadhyay, Thomas J Oldfield, Ardan Patwardhan, Ezra Peisach, Gaurav Sahni, Monica R Sekharan, Sanchayita Sen, Chenghua Shao, Oliver S Smart, Eldon L Ulrich, Reiko Yamashita, Martha Quesada, Jasmine Y Young, Haruki Nakamura, John L Markley, Helen M Berman, Stephen K Burley, Sameer Velankar, Gerard J Kleywegt
The Worldwide PDB recently launched a deposition, biocuration, and validation tool: OneDep. At various stages of OneDep data processing, validation reports for three-dimensional structures of biological macromolecules are produced. These reports are based on recommendations of expert task forces representing crystallography, nuclear magnetic resonance, and cryoelectron microscopy communities. The reports provide useful metrics with which depositors can evaluate the quality of the experimental data, the structural model, and the fit between them...
November 21, 2017: Structure
Mark A Nakasone, Timothy A Lewis, Olivier Walker, Anita Thakur, Wissam Mansour, Carlos A Castañeda, Jennifer L Goeckeler-Fried, Frank Parlati, Tsui-Fen Chou, Ortal Hayat, Daoning Zhang, Christina M Camara, Steven M Bonn, Urszula K Nowicka, Susan Krueger, Michael H Glickman, Jeffrey L Brodsky, Raymond J Deshaies, David Fushman
The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it...
November 15, 2017: Structure
Amandeep K Sangha, Jinhui Dong, Lauren Williamson, Takao Hashiguchi, Erica Ollmann Saphire, James E Crowe, Jens Meiler
An atomic-detail model of the Marburg virus glycoprotein in complex with a neutralizing human monoclonal antibody designated MR78 was constructed using Phenix.Rosetta starting from a 3.6Å crystallographic density map. The Asp at T6 in the HCDR3's bulged torso cannot form the canonical salt bridge as position T2 lacks an Arg or Lys residue. It instead engages in a hydrogen bond interaction with a Tyr contributed by the HCDR1 loop. This inter-CDR loop interaction stabilizes the bulged conformation needed for binding to the viral glycoprotein: a Tyr to Phe mutant displays a binding affinity reduced by a factor of at least 10...
November 14, 2017: Structure
Andreas Naschberger, Andrew Orry, Stefan Lechner, Matthew W Bowler, Didier Nurizzo, Mislav Novokmet, Markus A Keller, Gregor Oemer, Daniele Seppi, Martin Haslbeck, Kathrin Pansi, Hans Dieplinger, Bernhard Rupp
Afamin, a human plasma glycoprotein and putative transporter of hydrophobic molecules, has been shown to act as extracellular chaperone for poorly soluble, acylated Wnt proteins, forming a stable, soluble complex with functioning Wnt proteins. The 2.1-Å crystal structure of glycosylated human afamin reveals an almost exclusively hydrophobic binding cleft capable of harboring large hydrophobic moieties. Lipid analysis confirms the presence of lipids, and density in the primary binding pocket of afamin was modeled as palmitoleic acid, presenting the native O-acylation on serine 209 in human Wnt3a...
November 13, 2017: Structure
Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson
Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure (1)H, (15)N, and (13)C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out...
November 10, 2017: Structure
Manuela K Hospenthal, Dawid Zyla, Tiago R D Costa, Adam Redzej, Christoph Giese, James Lillington, Rudi Glockshuber, Gabriel Waksman
Adhesive chaperone-usher pili are long, supramolecular protein fibers displayed on the surface of many bacterial pathogens. The type 1 and P pili of uropathogenic Escherichia coli (UPEC) play important roles during urinary tract colonization, mediating attachment to the bladder and kidney, respectively. The biomechanical properties of the helical pilus rods allow them to reversibly uncoil in response to flow-induced forces, allowing UPEC to retain a foothold in the unique and hostile environment of the urinary tract...
November 7, 2017: Structure
Inokentijs Josts, Christopher James Stubenrauch, Grishma Vadlamani, Khedidja Mosbahi, Daniel Walker, Trevor Lithgow, Rhys Grinter
The translocation and assembly module (TAM) plays a role in the transport and insertion of proteins into the bacterial outer membrane. TamB, a component of this system spans the periplasmic space to engage with its partner protein TamA. Despite efforts to characterize the TAM, the structure and mechanism of action of TamB remained enigmatic. Here we present the crystal structure of TamB amino acids 963-1,138. This region represents half of the conserved DUF490 domain, the defining feature of TamB. TamB963-1138 consists of a concave, taco-shaped β sheet with a hydrophobic interior...
November 3, 2017: Structure
David Jan Drexler, Martina Müller, Carlos Alberto Rojas-Cordova, Adrian Maurice Bandera, Gregor Witte
The concentration of messenger molecules in bacterial cells needs to be tightly regulated. This can be achieved by either controlling the synthesis rate, degradation, or export by specific transporters, respectively. The regulation of the essential second messenger c-di-AMP is achieved by modulation of the diadenylate cyclase activity as well as by specific phosphodiesterases that hydrolyze c-di-AMP in the cell. We provide here structural and biochemical data on the DHH-type phosphodiesterase TmPDE (TM1595) from Thermotoga maritima...
October 24, 2017: Structure
Jailson Brito Querido, Eder Mancera-Martínez, Quentin Vicens, Anthony Bochler, Johana Chicher, Angelita Simonetti, Yaser Hashem
Kinetoplastids are potentially lethal protozoan pathogens affecting more than 20 million people worldwide. There is a critical need for more specific targets for the development of safer anti-kinetoplastid therapeutic molecules that can replace the scarce and highly cytotoxic current drugs. The kinetoplastid ribosome represents a potential therapeutic target due to its relative structural divergence when compared with its human counterpart. However, several kinetoplastid-specific ribosomal features remain uncharacterized...
October 13, 2017: Structure
Ling Xu, Lijun Wang, Junhui Peng, Fudong Li, Lijie Wu, Beibei Zhang, Mengqi Lv, Jiahai Zhang, Qingguo Gong, Rongguang Zhang, Xiaobing Zuo, Zhiyong Zhang, Jihui Wu, Yajun Tang, Yunyu Shi
CsdA has been proposed to be essential for the biogenesis of ribosome and gene regulation after cold shock. However, the structure of CsdA and the function of its long C-terminal regions are still unclear. Here, we solved all of the domain structures of CsdA and found two previously uncharacterized auxiliary domains: a dimerization domain (DD) and an RNA-binding domain (RBD). Small-angle X-ray scattering experiments helped to track the conformational flexibilities of the helicase core domains and C-terminal regions...
October 12, 2017: Structure
Dovile Januliene, Jacob Lauwring Andersen, Jeppe Achton Nielsen, Esben Meldgaard Quistgaard, Maria Hansen, Dorthe Strandbygaard, Arne Moeller, Claus Munck Petersen, Peder Madsen, Søren Skou Thirup
Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-Å resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released. The structure reveals an overall distortion of the 10-bladed β-propeller domain...
October 12, 2017: Structure
Djoshkun Shengjuler, Yan Mei Chan, Simou Sun, Ibrahim M Moustafa, Zhen-Lu Li, David W Gohara, Matthias Buck, Paul S Cremer, David D Boehr, Craig E Cameron
Some viruses use phosphatidylinositol phosphate (PIP) to mark membranes used for genome replication or virion assembly. PIP-binding motifs of cellular proteins do not exist in viral proteins. Molecular-docking simulations revealed a putative site of PIP binding to poliovirus (PV) 3C protein that was validated using nuclear magnetic resonance spectroscopy. The PIP-binding site was located on a highly dynamic α helix, which also functions in RNA binding. Broad PIP-binding activity was observed in solution using a fluorescence polarization assay or in the context of a lipid bilayer using an on-chip, fluorescence assay...
December 5, 2017: Structure
Ruth Cohen-Khait, Orly Dym, Shelly Hamer-Rogotner, Gideon Schreiber
Proteins have evolved to balance efficient binding of desired partners with rejection of unwanted interactions. To investigate the evolution of protein-protein interactions, we selected a random library of pre-stabilized TEM1 β-lactamase against wild-type TEM1 using yeast surface display. Three mutations were sufficient to achieve micromolar affinity binding between the two. The X-ray structure emphasized that the main contribution of the selected mutations was to modify the protein fold, specifically removing the N'-terminal helix, which consequently allowed protein coupling via a β-sheet-mediated interaction resembling amyloid interaction mode...
December 5, 2017: Structure
Hye-Jeong Yeo
Type 1 and P pili are important virulence factors of uropathogenic Escherichia coli, the leading cause of urinary tract infections. In this issue of Structure, Hospenthal et al. (2017) describe a near-atomic resolution cryo-EM structure of the type 1 pilus rod, providing molecular insights into rod uncoiling in two pili.
December 5, 2017: Structure
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