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66 items found (0 items not approved), displaying 31 to 40.[First/Prev] 1, 2, 3, 4, 5, 6, 7 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Structure of glycosylated NPC1 luminal domain C reveals insights into NPC2 and Ebola virus interactions Yuguang Zhao , Jingshan Ren , Karl Harlos , Dave Stuart Febs Letters 590 (5), 605-12 DOI: 10.1002/1873-3468.12089 PMID: 26846330 Open Access Show Abstract ▼ Abstract: Niemann-pick type C1 (NPC1) is an endo/lysosomal membrane protein involved in intracellular cholesterol trafficking, and its luminal domain C is an essential endosomal receptor for Ebola and Marburg viruses. We have determined the crystal structure of glycosylated NPC1 luminal domain C and find all seven possible sites are glycosylated. Mapping the disease mutations onto the glycosylated structure reveals a potential binding face for NPC2. Knowledge-based docking of NPC1 onto Ebola viral glycoprotein and sequence analysis of filovirus susceptible and refractory species reveals four critical residues, H418, Q421, F502 and F504, some or all of which are likely responsible for the species-specific susceptibility to the virus infection.	Feb 2016
I04-Macromolecular Crystallography	Crystal Structure of the Herpesvirus Nuclear Egress Complex Provides Insights into Inner Nuclear Membrane Remodeling Tzviya Zeev-ben-mordehai , Marion Weberruß , Michael Lorenz , Juliana Cheleski , Teresa Hellberg , Cathy Whittle , Kamel El omari , Daven Vasishtan , Kyle C. Dent , Karl Harlos , Kati Franzke , Christoph Hagen , Barbara G. Klupp , Wolfram Antonin , Thomas c. Mettenleiter , Kay Grünewald Cell Reports 13 (12), 2645 - 2652 DOI: 10.1016/j.celrep.2015.11.008 PMID: 26711332 Open Access Show Abstract ▼ Abstract: Although nucleo-cytoplasmic transport is typically mediated through nuclear pore complexes, herpesvirus capsids exit the nucleus via a unique vesicular pathway. Together, the conserved herpesvirus proteins pUL31 and pUL34 form the heterodimeric nuclear egress complex (NEC), which, in turn, mediates the formation of tight-fitting membrane vesicles around capsids at the inner nuclear membrane. Here, we present the crystal structure of the pseudorabies virus NEC. The structure revealed that a zinc finger motif in pUL31 and an extensive interaction network between the two proteins stabilize the complex. Comprehensive mutational analyses, characterized both in situ and in vitro, indicated that the interaction network is not redundant but rather complementary. Fitting of the NEC crystal structure into the recently determined cryoEM-derived hexagonal lattice, formed in situ by pUL31 and pUL34, provided details on the molecular basis of NEC coat formation and inner nuclear membrane remodeling.	Dec 2015
I03-Macromolecular Crystallography	Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing A. Mpakali , E. Saridakis , K. Harlos , Y. Zhao , A. Papakyriakou , P. Kokkala , D. Georgiadis , E. Stratikos The Journal Of Immunology 195 (6), 2842 - 2851 DOI: 10.4049/jimmunol.1501103 PMID: 26259583 Show Abstract ▼ Abstract: Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast number of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that prepares antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent. The N-terminal moiety of the peptide is located at the active site, positioned optimally for catalysis, whereas the C-terminal moiety of the peptide is stabilized along the extended internal cavity lodged between domains II and IV. Hydrophobic interactions and shape complementarity enhance peptide affinity beyond the catalytic site and support a limited selectivity model for antigenic peptide selection that may underlie the generation of complex immunopeptidomes.	Sep 2015
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan Tao-hsin Chang , Fu-lien Hsieh , Matthias Zebisch , Karl Harlos , Jonathan Elegheert , Edith Jones Elife 4 DOI: 10.7554/eLife.06554 PMID: 26158506 Diamond Proposal Number(s): [10627] Open Access Show Abstract ▼ Abstract: Wnt signalling regulates multiple processes including angiogenesis, inflammation, and tumorigenesis. Norrin (Norrie Disease Protein) is a cystine-knot like growth factor. Although unrelated to Wnt, Norrin activates the Wnt/β-catenin pathway. Signal complex formation involves Frizzled4 (Fz4), low-density lipoprotein receptor related protein 5/6 (Lrp5/6), Tetraspanin-12 and glycosaminoglycans (GAGs). Here, we report crystallographic and small-angle X-ray scattering analyses of Norrin in complex with Fz4 cysteine-rich domain (Fz4CRD), of this complex bound with GAG analogues, and of unliganded Norrin and Fz4CRD. Our structural, biophysical and cellular data, map Fz4 and putative Lrp5/6 binding sites to distinct patches on Norrin, and reveal a GAG binding site spanning Norrin and Fz4CRD. These results explain numerous disease-associated mutations. Comparison with the Xenopus Wnt8–mouse Fz8CRD complex reveals Norrin mimics Wnt for Frizzled recognition. The production and characterization of wild-type and mutant Norrins reported here open new avenues for the development of therapeutics to combat abnormal Norrin/Wnt signalling.	Jul 2015
I04-Macromolecular Crystallography	Structural Basis of Latrophilin-FLRT Interaction Verity Jackson , Daniel Del toro , Maria Carrasquero , Pietro Roversi , Karl Harlos , Rüdiger Klein , Elena Seiradake Structure DOI: 10.1016/j.str.2015.01.013 PMID: 25728924 Diamond Proposal Number(s): [10627] Open Access Show Abstract ▼ Abstract: Jackson et al. describe a crystal structure of mLPHN3 lectin and olfactomedin-like (Olf) domains, revealing the Olf b-propeller fold and calcium-binding site. Assays using HeLa cells and cortical neurons reveal a bi-functional role for Olf and its ligand FLRT, leading to HeLa cell adhesion and neuron repulsion.	Apr 2015
I02-Macromolecular Crystallography	Structural plasticity of Cid1 provides a basis for its distributive RNA terminal uridylyl transferase activity Luke Yates , Benjamin Durrant , S. Fleurdepine , Karl Harlos , C. J. Norbury , Robert Gilbert Nucleic Acids Research 43 (5), 2968 - 2979 DOI: 10.1093/nar/gkv122 PMID: 25712096 Diamond Proposal Number(s): [10627] Open Access Show Abstract ▼ Abstract: Terminal uridylyl transferases (TUTs) are respon- sible for the post-transcriptional addition of uridyl residues to RNA 3' ends, leading in some cases to altered stability. The Schizosaccharomyces pombe TUT Cid1 is a model enzyme that has been character- ized structurally at moderate resolution and provides insights into the larger and more complex mam- malian TUTs, ZCCHC6 and ZCCHC11. Here, we re- port a higher resolution (1.74 Angstroms) crystal structure of Cid1 that provides detailed evidence for uracil se- lection via the dynamic flipping of a single histidine residue. We also describe a novel closed conforma- tion of the enzyme that may represent an intermedi- ate stage in a proposed product ejection mechanism. The structural insights gained, combined with nor- mal mode analysis and biochemical studies, demon- strate that the plasticity of Cid1, particularly about a hinge region (N164N165), is essential for catalytic activity, and provide an explanation for its distribu- tive uridylyl transferase activity. We propose a model clarifying observed differences between the in vitro apparently processive activity and in vivo distributive monouridylylation activity of Cid1. We suggest that modulating the flexibility of such enzymesfor ex- ample by the binding of protein co-factorsmay al- low them alternatively to add single or multiple uridyl residues to the 3' termini of RNA molecules.	Mar 2015
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Improved crystallization and diffraction of caffeine-induced death suppressor protein 1 (Cid1) Luke A. Yates , Benjamin P. Durrant , Michael Barber , Karl Harlos , Sophie Fleurdépine , Chris J. Norbury , Robert Gilbert Acta Crystallographica Section F Structural Biology Communications 71 (3), 346 - 353 DOI: 10.1107/S2053230X15001351 PMID: 25760713 Diamond Proposal Number(s): [10627] Open Access Show Abstract ▼ Abstract: The post-transcriptional addition of uridines to the 3'-end of RNAs is an important regulatory process that is critical for coding and noncoding RNA stability. In fission yeast and metazoans this untemplated 3'-uridylylation is catalysed by a single family of terminal uridylyltransferases (TUTs) whose members are adapted to specific RNA targets. In Schizosaccharomyces pombe the TUT Cid1 is responsible for the uridylylation of polyadenylated mRNAs, targeting them for destruction. In metazoans, the Cid1 orthologues ZCCHC6 and ZCCHC11 uridylate histone mRNAs, targeting them for degradation, but also uridylate microRNAs, altering their maturation. Cid1 has been studied as a model TUT that has provided insights into the larger and more complex metazoan enzyme system. In this paper, two strategies are described that led to improvements both in the crystallogenesis of Cid1 and in the resolution of diffraction by ~1.5 Å. These advances have allowed high-resolution crystallographic studies of this TUT system to be initiated.	Mar 2015
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Four crystal structures of human LLT1, a ligand of human NKR-P1, in varied glycosylation and oligomerization states Tereza Skálová , Jan Bláha , Karl Harlos , Jarmila Duskova , Tomáš Koval' , Jan Stransky , Jindřich Hašek , Ondřej Vaněk , Jan Dohnalek Acta Crystallographica Section D Biological Crystallography 71, 578 - 591 DOI: 10.1107/S1399004714027928 PMID: 25760607 Open Access Show Abstract ▼ Abstract: Human LLT1 is a C-type lectin-like ligand of NKR-P1 (CD161, gene KLRB1), a C-type lectin-like receptor of natural killer cells. Using X-ray diffraction, the first experimental structures of human LLT1 were determined. Four structures of LLT1 under various conditions were determined: monomeric, dimeric deglycosylated after the first N-acetylglucosamine unit in two forms and hexameric with homogeneous GlcNAc2Man5 glycosylation. The dimeric form follows the classical dimerization mode of human CD69. The monomeric form keeps the same fold with the exception of the position of an outer part of the long loop region. The hexamer of glycosylated LLT1 consists of three classical dimers. The hexameric packing may indicate a possible mode of interaction of C-type lectin-like proteins in the glycosylated form.	Mar 2015
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	FLRT Structure: Balancing Repulsion and Cell Adhesion in Cortical and Vascular Development Elena Seiradake , Daniel Del toro , Daniel Nagel , Florian Cop , Ricarda Härtl , Tobias Ruff , Gönül Seyit-bremer , Karl Harlos , Ellen clare Border , Amparo Acker-palmer , Edith Jones , Rüdiger Klein Neuron 84 (2), 370 - 385 DOI: 10.1016/j.neuron.2014.10.008 PMID: 25374360 Diamond Proposal Number(s): [8423] Open Access Show Abstract ▼ Abstract: FLRTs are broadly expressed proteins with the unique property of acting as homophilic cell adhesion molecules and as heterophilic repulsive ligands of Unc5/Netrin receptors. How these functions direct cell behavior and the molecular mechanisms involved remain largely unclear. Here we use X-ray crystallography to reveal the distinct structural bases for FLRT-mediated cell adhesion and repulsion in neurons. We apply this knowledge to elucidate FLRT functions during cortical development. We show that FLRTs regulate both the radial migration of pyramidal neurons, as well as their tangential spread. Mechanistically, radial migration is controlled by repulsive FLRT2-Unc5D interactions, while spatial organization in the tangential axis involves adhesive FLRT-FLRT interactions. Further, we show that the fundamental mechanisms of FLRT adhesion and repulsion are conserved between neurons and vascular endothelial cells. Our results reveal FLRTs as powerful guidance factors with structurally encoded repulsive and adhesive surfaces.	Oct 2014
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Unexpected structure for the N-terminal domain of hepatitis C virus envelope glycoprotein E1 Kamel El Omari , Oleg Iourin , Jan Kadlec , Geoff Sutton , Karl Harlos , Jonathan M. Grimes , David I. Stuart Nature Communications 5 DOI: 10.1038/ncomms5874 PMID: 25224686 Diamond Proposal Number(s): [8423] Open Access Show Abstract ▼ Abstract: Hepatitis C virus (HCV) infection remains a major health problem worldwide. HCV entry into host cells and membrane fusion are achieved by two envelope glycoproteins, E1 and E2. We report here the 3.5-Å resolution crystal structure of the N-terminal domain of the HCV E1 ectodomain, which reveals a complex network of covalently linked intertwined homodimers that do not harbour the expected truncated class II fusion protein fold.	Sep 2014

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