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https://www.readbyqxmd.com/read/28528777/fcab-her2-interaction-a-m%C3%A3-nage-%C3%A3-trois-lessons-from-x-ray-and-solution-studies
#1
Elisabeth Lobner, Anne-Sophie Humm, Kathrin Göritzer, Georg Mlynek, Martin G Puchinger, Christoph Hasenhindl, Florian Rüker, Michael W Traxlmayr, Kristina Djinović-Carugo, Christian Obinger
The crystallizable fragment (Fc) of the immunoglobulin class G (IgG) is an attractive scaffold for the design of novel therapeutics. Upon engineering the C-terminal loops in the CH3 domains, Fcabs (Fc domain with antigen-binding sites) can be designed. We present the first crystal structures of Fcabs, i.e., of the HER2-binding clone H10-03-6 having the AB and EF loop engineered and the stabilized version STAB19 derived by directed evolution. Comparison with the crystal structure of the Fc wild-type protein reveals conservation of the overall domain structures but significant differences in EF-loop conformations...
May 18, 2017: Structure
https://www.readbyqxmd.com/read/28528776/structural-basis-of-tpr-mediated-oligomerization-and-activation-of-oncogenic-fusion-kinases
#2
Kuntal Pal, Abhishek Bandyopadhyay, X Edward Zhou, Qingping Xu, David P Marciano, Joseph S Brunzelle, Smitha Yerrum, Patrick R Griffin, George Vande Woude, Karsten Melcher, H Eric Xu
The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2-142), the MET fusion partner of oncogenic TPR-MET. TPR(2-142) contains a continuous 124-residue α helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature...
May 18, 2017: Structure
https://www.readbyqxmd.com/read/28528775/structural-basis-for-apelin-control-of-the-human-apelin-receptor
#3
Yingli Ma, Yang Yue, Yanbin Ma, Qing Zhang, Qingtong Zhou, Yunpeng Song, Yuqing Shen, Xun Li, Xiaochuan Ma, Chao Li, Michael A Hanson, Gye Won Han, E Allen Sickmier, Gayathri Swaminath, Suwen Zhao, Raymond C Stevens, Liaoyuan A Hu, Wenge Zhong, Mingqiang Zhang, Fei Xu
Apelin receptor (APJR) is a key regulator of human cardiovascular function and is activated by two different endogenous peptide ligands, apelin and Elabela, each with different isoforms diversified by length and amino acid sequence. Here we report the 2.6-Å resolution crystal structure of human APJR in complex with a designed 17-amino-acid apelin mimetic peptide agonist. The structure reveals that the peptide agonist adopts a lactam constrained curved two-site ligand binding mode. Combined with mutation analysis and molecular dynamics simulations with apelin-13 binding to the wild-type APJR, this structure provides a mechanistic understanding of apelin recognition and binding specificity...
May 11, 2017: Structure
https://www.readbyqxmd.com/read/28502782/time-resolved-x-ray-solution-scattering-reveals-the-structural-photoactivation-of-a-light-oxygen-voltage-photoreceptor
#4
Oskar Berntsson, Ralph P Diensthuber, Matthijs R Panman, Alexander Björling, Ashley J Hughes, Léocadie Henry, Stephan Niebling, Gemma Newby, Marianne Liebi, Andreas Menzel, Robert Henning, Irina Kosheleva, Andreas Möglich, Sebastian Westenhoff
Light-oxygen-voltage (LOV) receptors are sensory proteins controlling a wide range of organismal adaptations in multiple kingdoms of life. Because of their modular nature, LOV domains are also attractive for use as optogenetic actuators. A flavin chromophore absorbs blue light, forms a bond with a proximal cysteine residue, and induces changes in the surroundings. There is a gap of knowledge on how this initial signal is relayed further through the sensor to the effector module. To characterize these conformational changes, we apply time-resolved X-ray scattering to the homodimeric LOV domain from Bacillus subtilis YtvA...
May 8, 2017: Structure
https://www.readbyqxmd.com/read/28479062/structural-insight-into-ubiquitin-like-protein-recognition-and-oligomeric-states-of-jamm-mpn-proteases
#5
Shiyun Cao, Sylvain Engilberge, Eric Girard, Frank Gabel, Bruno Franzetti, Julie A Maupin-Furlow
JAMM/MPN(+) metalloproteases cleave (iso)peptide bonds C-terminal to ubiquitin (Ub) and ubiquitin-like protein (Ubl) domains and typically require association with protein partners for activity, which has limited a molecular understanding of enzyme function. To provide an insight, we solved the X-ray crystal structures of a catalytically active Pyrococcus furiosus JAMM/MPN(+) metalloprotease (PfJAMM1) alone and in complex with a Ubl (PfSAMP2) to 1.7- to 1.9-Å resolution. PfJAMM1 was found to have a redox sensitive dimer interface...
May 4, 2017: Structure
https://www.readbyqxmd.com/read/28479061/crystal-structures-of-human-glyr%C3%AE-3-bound-to-ivermectin
#6
Xin Huang, Hao Chen, Paul L Shaffer
Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive...
May 4, 2017: Structure
https://www.readbyqxmd.com/read/28479063/the-architecture-of-the-anbu-complex-reflects-an-evolutionary-intermediate-at-the-origin-of-the-proteasome-system
#7
Adrian C D Fuchs, Vikram Alva, Lorena Maldoner, Reinhard Albrecht, Marcus D Hartmann, Jörg Martin
Proteasomes are self-compartmentalizing proteases that function at the core of the cellular protein degradation machinery in eukaryotes, archaea, and some bacteria. Although their evolutionary history is under debate, it is thought to be linked to that of the bacterial protease HslV and the hypothetical bacterial protease Anbu (ancestral beta subunit). Here, together with an extensive bioinformatic analysis, we present the first biophysical characterization of Anbu. Anbu forms a dodecameric complex with a unique architecture that was only accessible through the combination of X-ray crystallography and small-angle X-ray scattering...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28479060/the-highly-dynamic-nature-of-erdj5-is-key-to-efficient-elimination-of-aberrant-protein-oligomers-through-er-associated-degradation
#8
Ken-Ichi Maegawa, Satoshi Watanabe, Kentaro Noi, Masaki Okumura, Yuta Amagai, Michio Inoue, Ryo Ushioda, Kazuhiro Nagata, Teru Ogura, Kenji Inaba
ERdj5, composed of an N-terminal J domain followed by six thioredoxin-like domains, is the largest protein disulfide isomerase family member and functions as an ER-localized disulfide reductase that enhances ER-associated degradation (ERAD). Our previous studies indicated that ERdj5 comprises two regions, the N- and C-terminal clusters, separated by a linker loop and with distinct functional roles in ERAD. We here present a new crystal structure of ERdj5 with a largely different cluster arrangement relative to that in the original crystal structure...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28467915/revealing-the-inter-module-interactions-of-multi-modular-nonribosomal-peptide-synthetases
#9
J Shaun Lott, T Verne Lee
Nonribosomal peptide synthetase (NRPS) enzymes are large modular proteins involved in the biosynthesis of many important pharmaceuticals such as penicillin and cyclosporin. In this issue of Structure, Tarry et al. (2017) use X-ray crystallography and electron microscopy to shed light on the inter-module interactions that underpin the complex function of these enzymes.
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28467914/room-temperature-x-ray-crystallography-reveals-conformational-heterogeneity-of-engineered-proteins
#10
Thomas Szyperski
In this issue of Structure, Biel et al. (2017) present multi-conformer analyses from room temperature X-ray data of two ubiquitin phage display variants binding deubiquitinase USP7. The first contains core mutations. The second matured variant contains additional surface mutations. Alternate conformations detected in the core mutant were removed by maturation.
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28434917/conformational-dynamics-and-allostery-in-e2-e3-interactions-drive-ubiquitination-gp78-and-ube2g2
#11
Kalyan S Chakrabarti, Jess Li, Ranabir Das, R Andrew Byrd
Conformational dynamics plays a fundamental role in molecular recognition and activity in enzymes. The ubiquitin-conjugating enzyme (E2) Ube2g2 functions with the ubiquitin ligase (E3) gp78 to assemble poly-ubiquitin chains on target substrates. Two domains in gp78, RING and G2BR, bind to two distant regions of Ube2g2, and activate it for ubiquitin (Ub) transfer. G2BR increases the affinity between the RING and Ube2g2 by 50-fold, while the RING catalyzes the transfer of Ub from the Ube2g2∼Ub conjugate. How G2BR and RING activate Ube2g2 is unclear...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28434916/the-tetrameric-plant-lectin-banlec-neutralizes-hiv-through-bidentate-binding-to-specific-viral-glycans
#12
Jonathan T S Hopper, Stephen Ambrose, Oliver C Grant, Stefanie A Krumm, Timothy M Allison, Matteo T Degiacomi, Mark D Tully, Laura K Pritchard, Gabriel Ozorowski, Andrew B Ward, Max Crispin, Katie J Doores, Robert J Woods, Justin L P Benesch, Carol V Robinson, Weston B Struwe
Select lectins have powerful anti-viral properties that effectively neutralize HIV-1 by targeting the dense glycan shield on the virus. Here, we reveal the mechanism by which one of the most potent lectins, BanLec, achieves its inhibition. We identify that BanLec recognizes a subset of high-mannose glycans via bidentate interactions spanning the two binding sites present on each BanLec monomer that were previously considered separate carbohydrate recognition domains. We show that both sites are required for high-affinity glycan binding and virus neutralization...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28434915/x-ray-crystallography-and-electron-microscopy-of-cross-and-multi-module-nonribosomal-peptide-synthetase-proteins-reveal-a-flexible-architecture
#13
Michael J Tarry, Asfarul S Haque, Khanh Huy Bui, T Martin Schmeing
Nonribosomal peptide synthetases (NRPS) are macromolecular machines that produce peptides with diverse activities. Structural information exists for domains, didomains, and even modules, but little is known about higher-order organization. We performed a multi-technique study on constructs from the dimodular NRPS DhbF. We determined a crystal structure of a cross-module construct including the adenylation (A) and peptidyl carrier protein (PCP) domains from module 1 and the condensation domain from module 2, complexed with an adenosine-vinylsulfonamide inhibitor and an MbtH-like protein (MLP)...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28434914/full-length-oligomeric-structure-of-wzz-determined-by-cryoelectron-microscopy-reveals-insights-into-membrane-bound-states
#14
Richard F Collins, Vasileios Kargas, Brad R Clarke, C Alistair Siebert, Daniel K Clare, Peter J Bond, Chris Whitfield, Robert C Ford
Wzz is an integral inner membrane protein involved in regulating the length of lipopolysaccharide O-antigen glycans and essential for the virulence of many Gram-negative pathogens. In all Wzz homologs, the large periplasmic domain is proposed to be anchored by two transmembrane helices, but no information is available for the transmembrane and cytosolic domains. Here we have studied purified oligomeric Wzz complexes using cryoelectron microscopy and resolved the transmembrane regions within a semi-continuous detergent micelle...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28416112/flexibility-and-design-conformational-heterogeneity-along-the-evolutionary-trajectory-of-a-redesigned-ubiquitin
#15
Justin T Biel, Michael C Thompson, Christian N Cunningham, Jacob E Corn, James S Fraser
Although protein design has been used to introduce new functions, designed variants generally only function as well as natural proteins after rounds of laboratory evolution. One possibility for this pattern is that designed mutants frequently sample nonfunctional conformations. To test this idea, we exploited advances in multiconformer modeling of room-temperature X-ray data collection on redesigned ubiquitin variants selected for increasing binding affinity to the deubiquitinase USP7. Initial core mutations disrupt natural packing and lead to increased flexibility...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28416111/structural-analysis-reveals-features-of-ribosome-assembly-factor-nsa1-wdr74-important-for-localization-and-interaction-with-rix7-nvl2
#16
Yu-Hua Lo, Erin M Romes, Monica C Pillon, Mack Sobhany, Robin E Stanley
Ribosome assembly is a complex process that requires hundreds of essential assembly factors, including Rix7 (NVL2 in mammals) and Nsa1 (WDR74 in mammals). Rix7 is a type II double ring, AAA-ATPase, which is closely related to the well-known Cdc48/p97. Previous studies in Saccharomyces cerevisiae suggest that Rix7 mediates the release of Nsa1 from nucleolar pre-60S particles; however, the underlying mechanisms of this release are unknown. Through multiple structural analyses we show that S. cerevisiae Nsa1 is composed of an N-terminal seven-bladed WD40 domain followed by a lysine-rich C terminus that extends away from the WD40 domain and is required for nucleolar localization...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28416110/structural-basis-for-kinase-mediated-macrolide-antibiotic-resistance
#17
Desiree H Fong, David L Burk, Jonathan Blanchet, Amy Y Yan, Albert M Berghuis
The macrolides are a class of antibiotic, characterized by a large macrocyclic lactone ring that can be inactivated by macrolide phosphotransferase enzymes. We present structures for MPH(2')-I and MPH(2')-II in the apo state, and in complex with GTP analogs and six different macrolides. These represent the first structures from the two main classes of macrolide phosphotransferases. The structures show that the enzymes are related to the aminoglycoside phosphotransferases, but are distinguished from them by the presence of a large interdomain linker that contributes to an expanded antibiotic binding pocket...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28392261/bound-waters-mediate-binding-of-diverse-substrates-to-a-ubiquitin-ligase
#18
Juliana Muñoz-Escobar, Edna Matta-Camacho, Cordelia Cho, Guennadi Kozlov, Kalle Gehring
The N-end rule pathway controls the half-life of proteins based on their N-terminal residue. Positively charged type 1 N-degrons are recognized by a negatively charged pocket on the Zn finger named the UBR box. Here, we show that the UBR box is rigid, but bound water molecules in the pocket provide the structural plasticity required to bind different positively charged amino acids. Ultra-high-resolution crystal structures of arginine, histidine, and methylated arginine reveal that water molecules mediate the binding of N-degron peptides...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28392260/hybrid-mass-spectrometry-approaches-to-determine-how-l-histidine-feedback-regulates-the-enzyzme-mtatp-phosphoribosyltransferase
#19
Kamila J Pacholarz, Rebecca J Burnley, Thomas A Jowitt, Victoria Ordsmith, João Pedro Pisco, Massimiliano Porrini, Gérald Larrouy-Maumus, Rachel A Garlish, Richard J Taylor, Luiz Pedro Sório de Carvalho, Perdita E Barran
MtATP-phosphoribosyltransferase (MtATP-PRT) is an enzyme catalyzing the first step of the biosynthesis of L-histidine in Mycobacterium tuberculosis, and proposed to be regulated via an allosteric mechanism. Native mass spectrometry (MS) reveals MtATP-PRT to exist as a hexamer. Conformational changes induced by L-histidine binding and the influence of buffer pH are determined with ion mobility MS, hydrogen deuterium exchange (HDX) MS, and analytical ultracentrifugation. The experimental collision cross-section ((DT)CCSHe) decreases from 76...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28392259/active-site-flexibility-and-substrate-specificity-in-a-bacterial-virulence-factor-crystallographic-snapshots-of-an-epoxide-hydrolase
#20
Kelli L Hvorecny, Christopher D Bahl, Seiya Kitamura, Kin Sing Stephen Lee, Bruce D Hammock, Christophe Morisseau, Dean R Madden
Pseudomonas aeruginosa secretes an epoxide hydrolase with catalytic activity that triggers degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and perturbs other host defense networks. Targets of this CFTR inhibitory factor (Cif) are largely unknown, but include an epoxy-fatty acid. In this class of signaling molecules, chirality can be an important determinant of physiological output and potency. Here we explore the active-site chemistry of this two-step α/β-hydrolase and its implications for an emerging class of virulence enzymes...
May 2, 2017: Structure
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