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Kala Bharath Pilla, Gottfried Otting, Thomas Huber
Computational and nuclear magnetic resonance hybrid approaches provide efficient tools for 3D structure determination of small proteins, but currently available algorithms struggle to perform with larger proteins. Here we demonstrate a new computational algorithm that assembles the 3D structure of a protein from its constituent super-secondary structural motifs (Smotifs) with the help of pseudocontact shift (PCS) restraints for backbone amide protons, where the PCSs are produced from different metal centers...
February 16, 2017: Structure
Chenghua Shao, Huanwang Yang, John D Westbrook, Jasmine Y Young, Christine Zardecki, Stephen K Burley
Following deployment of an augmented validation system by the Worldwide Protein Data Bank (wwPDB) partnership, the quality of crystal structures entering the PDB has improved. Of significance are improvements in quality measures now prominently displayed in the wwPDB validation report. Comparisons of PDB depositions made before and after introduction of the new reporting system show improvements in quality measures relating to pairwise atom-atom clashes, side-chain torsion angle rotamers, and local agreement between the atomic coordinate structure model and experimental electron density data...
February 15, 2017: Structure
Jacob L W Morgan, Justin F Acheson, Jochen Zimmer
Type-1 secretion systems (T1SSs) represent a widespread mode of protein secretion across the cell envelope in Gram-negative bacteria. The T1SS is composed of an inner-membrane ABC transporter, a periplasmic membrane-fusion protein, and an outer-membrane porin. These three components assemble into a complex spanning both membranes and providing a conduit for the translocation of unfolded polypeptides. We show that ATP hydrolysis and assembly of the entire T1SS complex is necessary for protein secretion. Furthermore, we present a 3...
February 15, 2017: Structure
Joe G Greener, Ioannis Filippis, Michael J E Sternberg
The related concepts of protein dynamics, conformational ensembles and allostery are often difficult to study with molecular dynamics (MD) due to the timescales involved. We present ExProSE (Exploration of Protein Structural Ensembles), a distance geometry-based method that generates an ensemble of protein structures from two input structures. ExProSE provides a unified framework for the exploration of protein structure and dynamics in a fast and accessible way. Using a dataset of apo/holo pairs it is shown that existing coarse-grained methods often cannot span large conformational changes...
February 7, 2017: Structure
Jasmine Y Young, John D Westbrook, Zukang Feng, Raul Sala, Ezra Peisach, Thomas J Oldfield, Sanchayita Sen, Aleksandras Gutmanas, David R Armstrong, John M Berrisford, Li Chen, Minyu Chen, Luigi Di Costanzo, Dimitris Dimitropoulos, Guanghua Gao, Sutapa Ghosh, Swanand Gore, Vladimir Guranovic, Pieter M S Hendrickx, Brian P Hudson, Reiko Igarashi, Yasuyo Ikegawa, Naohiro Kobayashi, Catherine L Lawson, Yuhe Liang, Steve Mading, Lora Mak, M Saqib Mir, Abhik Mukhopadhyay, Ardan Patwardhan, Irina Persikova, Luana Rinaldi, Eduardo Sanz-Garcia, Monica R Sekharan, Chenghua Shao, G Jawahar Swaminathan, Lihua Tan, Eldon L Ulrich, Glen van Ginkel, Reiko Yamashita, Huanwang Yang, Marina A Zhuravleva, Martha Quesada, Gerard J Kleywegt, Helen M Berman, John L Markley, Haruki Nakamura, Sameer Velankar, Stephen K Burley
OneDep, a unified system for deposition, biocuration, and validation of experimentally determined structures of biological macromolecules to the PDB archive, has been developed as a global collaboration by the worldwide PDB (wwPDB) partners. This new system was designed to ensure that the wwPDB could meet the evolving archiving requirements of the scientific community over the coming decades. OneDep unifies deposition, biocuration, and validation pipelines across all wwPDB, EMDB, and BMRB deposition sites with improved focus on data quality and completeness in these archives, while supporting growth in the number of depositions and increases in their average size and complexity...
February 3, 2017: Structure
Paula Upla, Seung Joong Kim, Parthasarathy Sampathkumar, Kaushik Dutta, Sean M Cahill, Ilan E Chemmama, Rosemary Williams, Jeffrey B Bonanno, William J Rice, David L Stokes, David Cowburn, Steven C Almo, Andrej Sali, Michael P Rout, Javier Fernandez-Martinez
The membrane ring that equatorially circumscribes the nuclear pore complex (NPC) in the perinuclear lumen of the nuclear envelope is composed largely of Pom152 in yeast and its ortholog Nup210 (or Gp210) in vertebrates. Here, we have used a combination of negative-stain electron microscopy, nuclear magnetic resonance, and small-angle X-ray scattering methods to determine an integrative structure of the ∼120 kDa luminal domain of Pom152. Our structural analysis reveals that the luminal domain is formed by a flexible string-of-pearls arrangement of nine repetitive cadherin-like Ig-like domains, indicating an evolutionary connection between NPCs and the cell adhesion machinery...
February 2, 2017: Structure
Alexandra C Chadwick, Davin R Jensen, Paul J Hanson, Philip T Lange, Sarah C Proudfoot, Francis C Peterson, Brian F Volkman, Daisy Sahoo
The interaction of high-density lipoprotein (HDL) with its receptor, scavenger receptor BI (SR-BI), is critical for lowering plasma cholesterol levels and reducing the risk for cardiovascular disease. The HDL/SR-BI complex facilitates delivery of cholesterol into cells and is likely mediated by receptor dimerization. This work describes the use of nuclear magnetic resonance (NMR) spectroscopy to generate the first high-resolution structure of the C-terminal transmembrane domain of SR-BI. This region of SR-BI harbors a leucine zipper dimerization motif, which when mutated impairs the ability of the receptor to bind HDL and mediate cholesterol delivery...
January 31, 2017: Structure
Jing Jie, Frank Löhr, Elisar Barbar
Dynactin and NudE/Nudel are prominent regulators of cytoplasmic dynein motility and cargo-binding activities. Both interact with the intrinsically disordered N-terminal domain of dynein intermediate chain (IC), which also contains phosphorylation sites that apparently regulate these interactions. Nuclear magnetic resonance and isothermal calorimetry studies demonstrate that the Ser84 phosphorylation site identified in cells is in a disordered linker distant from the N-terminal helix that contains both the dynactin- and the Nudel-binding interfaces...
January 31, 2017: Structure
David Pulido, Sadaf-Ahmahni Hussain, Erhard Hohenester
Laminins are cell-adhesive glycoproteins that are essential for basement membrane assembly and function. Integrins are important laminin receptors, but their binding site on the heterotrimeric laminins is poorly defined structurally. We report the crystal structure at 2.13 Å resolution of a minimal integrin-binding fragment of mouse laminin-111, consisting of ∼50 residues of α1β1γ1 coiled coil and the first three laminin G-like (LG) domains of the α1 chain. The LG domains adopt a triangular arrangement, with the C terminus of the coiled coil situated between LG1 and LG2...
January 20, 2017: Structure
Aleksandra Usenik, Miha Renko, Marko Mihelič, Nataša Lindič, Jure Borišek, Andrej Perdih, Gregor Pretnar, Uwe Müller, Dušan Turk
Bacterial cell wall proteins play crucial roles in cell survival, growth, and environmental interactions. In Gram-positive bacteria, cell wall proteins include several types that are non-covalently attached via cell wall binding domains. Of the two conserved surface-layer (S-layer)-anchoring modules composed of three tandem SLH or CWB2 domains, the latter have so far eluded structural insight. The crystal structures of Cwp8 and Cwp6 reveal multi-domain proteins, each containing an embedded CWB2 module. It consists of a triangular trimer of Rossmann-fold CWB2 domains, a feature common to 29 cell wall proteins in Clostridium difficile 630...
January 20, 2017: Structure
Xiaoling Xie, Daniel Baird, Kimberly Bowen, Vladimir Capka, Jinyun Chen, Gregg Chenail, YoungShin Cho, Julia Dooley, Ali Farsidjani, Pascal Fortin, Darcy Kohls, Raviraj Kulathila, Fallon Lin, Daniel McKay, Lindsey Rodrigues, David Sage, Simon van der Plas, Kirk Wright, Ming Xu, Hong Yin, Julian Levell, Raymond A Pagliarini
Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1(R132H) mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity...
January 18, 2017: Structure
Tariq Ahmad Najar, Shruti Khare, Rajesh Pandey, Satish K Gupta, Raghavan Varadarajan
We describe a facile method for mapping protein:ligand binding sites and conformational epitopes. The method uses a combination of Cys scanning mutagenesis, chemical labeling, and yeast surface display. While Ala scanning is widely used for similar purposes, often mutation to Ala (or other amino acids) has little effect on binding, except at hotspot residues. Many residues in physical contact with a binding partner are insensitive to substitution with Ala. In contrast, we show that labeling of Cys residues in a binding site consistently abrogates binding...
January 18, 2017: Structure
Tsung-Wei Su, Chao-Yu Yang, Wen-Pin Kao, Bai-Jiun Kuo, Shan-Meng Lin, Jung-Yaw Lin, Yu-Chih Lo, Su-Chang Lin
Death domain (DD)-fold assemblies play a crucial role in regulating the signaling to cell survival or death. Here we report the crystal structure of the caspase recruitment domain (CARD)-CARD disk of the human apoptosome. The structure surprisingly reveals that three 1:1 Apaf-1:procaspase-9 CARD protomers form a novel helical DD-fold assembly on the heptameric wheel-like platform of the apoptosome. The small-angle X-ray scattering and multi-angle light scattering data also support that three protomers could form an oligomeric complex similar to the crystal structure...
January 11, 2017: Structure
Jacob A McPhail, Erik H Ottosen, Meredith L Jenkins, John E Burke
Phosphatidylinositol 4-kinase III beta (PI4KIIIβ) is an essential enzyme in mediating membrane transport, and plays key roles in facilitating viral infection. Many pathogenic positive-sense single-stranded RNA viruses activate PI4KIIIβ to generate phosphatidylinositol 4-phosphate (PI4P)-enriched organelles for viral replication. The molecular basis for PI4KIIIβ activation during viral infection has remained largely unclear. We describe the biochemical reconstitution and characterization of the complex of PI4KIIIβ with the Golgi protein Acyl-coenzyme A binding domain containing protein 3 (ACBD3) and Aichi virus 3A protein on membranes...
December 7, 2016: Structure
Erik W Hartwick, Brian T Wimberly
The assembly of eukaryotic ribosomes requires about 200 assembly factors promoting RNA modification, folding, cleavage, and ribosomal protein association. In this issue of Structure, Johnson et al. (2017) report structures of several late-stage intermediates of pre-40S ribosomal subunit assembly. This work provides detailed testable insights into assembly factor function.
February 7, 2017: Structure
Igor B Zhulin
In this issue of Structure, Lynch et al. (2017) reveal that the interaction between two key proteins in the bacterial flagellar motor results in a shared structural domain. This unusual arrangement keeps the corresponding genes together through the course of evolution.
February 7, 2017: Structure
Peter C Angeletti
In this issue of Structure, Guan et al. (2017) describe cryo-EM mapping of human papillomavirus 16 (HPV16) capsids that propose locations for L2 and heparin binding sites. The high resolution of the modern cryo-EM methods (in this case down to 4.3 Å) opens great opportunities to probe conformational changes that take place during virus-receptor binding.
February 7, 2017: Structure
Sandra Markovic-Mueller, Edward Stuttfeld, Mayanka Asthana, Tobias Weinert, Spencer Bliven, Kenneth N Goldie, Kaisa Kisko, Guido Capitani, Kurt Ballmer-Hofer
Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here, we describe the structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A at 4 Å resolution...
February 7, 2017: Structure
He Song, Xianyang Fang, Lan Jin, Gary X Shaw, Yun-Xing Wang, Xinhua Ji
Double-stranded RNA (dsRNA)-specific RNase III proteins are required for RNA maturation and gene regulation. The mechanism of prokaryotic RNase IIIs has been well characterized, but how eukaryotic RNase IIIs (exemplified by Rnt1p, Drosha, and Dicer) work is less clear. Recently, we reported the crystal structure of Rnt1p in complex with RNA, revealing a double-ruler mechanism for substrate selection. Here, we present more structures of Rnt1p, either RNA free or RNA bound, featuring two major conformations of the enzyme...
February 7, 2017: Structure
Ruodan Nan, Christopher M Furze, David W Wright, Jayesh Gor, Russell Wallis, Stephen J Perkins
The lectin pathway of complement is activated by complexes comprising a recognition component (mannose-binding lectin, serum ficolins, collectin-LK or collectin-K1) and a serine protease (MASP-1 or MASP-2). MASP-1 activates MASP-2, and MASP-2 cleaves C4 and C4b-bound C2. To clarify activation, new crystal structures of Ca(2+)-bound MASP dimers were determined, together with their solution structures from X-ray scattering, analytical ultracentrifugation, and atomistic modeling. Solution structures of the CUB1-EGF-CUB2 dimer of each MASP indicate that the two CUB2 domains were tilted by as much as 90° compared with the crystal structures, indicating considerable flexibility at the EGF-CUB2 junction...
February 7, 2017: Structure
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