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Qiang Chen, Marta M Wells, Tommy S Tillman, Monica N Kinde, Aina Cohen, Yan Xu, Pei Tang
The structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC co-crystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6') and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants...
November 26, 2016: Structure
Shan-Meng Lin, Su-Chang Lin, Jhen-Yi Hong, Tsung-Wei Su, Bai-Jiun Kuo, Wei-Hsin Chang, Yi-Fan Tu, Yu-Chih Lo
Recognition of linear polyubiquitin by specific ubiquitin-binding proteins plays an important role in mediating nuclear factor-κB (NF-κB) signaling. A20 binding proteins, ABINs, recognize linear polyubiquitin and A20 through UBAN and AHD1, respectively, for the inhibition of NF-κB activation. Here we report the crystal structure of the AHD1-UBAN fragment of ABIN2 in complex with linear tri-ubiquitin, which reveals a 2:1 stoichiometry of the complex. Structural analyses together with mutagenesis, pull-down, and isothermal titration calorimetry assays show that the hABIN2:tri-ubiquitin interaction is mainly through the primary ubiquitin-binding site, and also through the secondary ubiquitin-binding site under a high local protein concentration...
November 24, 2016: Structure
Dilraj Lama, Mohan R Pradhan, Christopher J Brown, Rohan S Eapen, Thomas L Joseph, Chee-Keong Kwoh, David P Lane, Chandra S Verma
Ligand binding pockets in proteins contain water molecules, which play important roles in modulating protein-ligand interactions. Available crystallographic data for the 5' mRNA cap-binding pocket of the translation initiation factor protein eIF4E shows several structurally conserved waters, which also persist in molecular dynamics simulations. These waters engage an intricate hydrogen-bond network between the cap and protein. Two crystallographic waters in the cleft of the pocket show a high degree of conservation and bridge two residues, which are part of an evolutionarily conserved scaffold...
November 24, 2016: Structure
Scott J Eron, Kishore Raghupathi, Jeanne A Hardy
Caspases, the cysteine proteases that execute apoptosis, are tightly regulated via phosphorylation by a series of kinases. Although all apoptotic caspases work in concert to promote apoptosis, different kinases regulate individual caspases. Several sites of caspase-7 phosphorylation have been reported, but without knowing the molecular details, it has been impossible to exploit or control these complex interactions, which normally prevent unwanted proliferation. During dysregulation, PAK2 kinase plays an alternative anti-apoptotic role, phosphorylating caspase-7 and promoting unfettered cell growth and chemotherapeutic resistance...
November 22, 2016: Structure
Eva S Cunha, Pedro Sfriso, Adriana L Rojas, Adam Hospital, Modesto Orozco, Nicola G A Abrescia
Hepatitis C virus (HCV) enters into human hepatocytes via tetraspanin hCD81. HCV glycoprotein E2 recognizes the "head" subdomain of the large extracellular loop (LEL) of CD81 (hCD81LEL), but the precise mechanism of virus cell attachment and entry remains elusive. Here, by combining the structural analysis of a conspicuous number of crystallized CD81LEL molecules with molecular dynamics simulations, we show that the conformational plasticity of the hCD81LEL head subdomain is a molecular property of the receptor...
November 21, 2016: Structure
Tat Cheung Cheng, Ildikó V Akey, Shujun Yuan, Zhiheng Yu, Steven J Ludtke, Christopher W Akey
In Drosophila, the Apaf-1-related killer (Dark) forms an apoptosome that activates procaspases. To investigate function, we have determined a near-atomic structure of Dark double rings using cryo-electron microscopy. We then built a nearly complete model of the apoptosome that includes 7- and 8-blade β-propellers. We find that the preference for dATP during Dark assembly may be governed by Ser325, which is in close proximity to the 2' carbon of the deoxyribose ring. Interestingly, β-propellers in V-shaped domains of the Dark apoptosome are more widely separated, relative to these features in the Apaf-1 apoptosome...
November 16, 2016: Structure
Erika Pellegrini, Andrés Palencia, Laurence Braun, Ulrike Kapp, Alexandre Bougdour, Hassan Belrhali, Matthew W Bowler, Mohamed-Ali Hakimi
The causative agent of toxoplasmosis, the intracellular parasite Toxoplasma gondii, delivers a protein, GRA24, into the cells it infects that interacts with the mitogen-activated protein (MAP) kinase p38α (MAPK14), leading to activation and nuclear translocation of the host kinase and a subsequent inflammatory response that controls the progress of the parasite. The purification of a recombinant complex of GRA24 and human p38α has allowed the molecular basis of this activation to be determined. GRA24 is shown to be intrinsically disordered, binding two kinases that act independently, and is the only factor required to bypass the canonical mitogen-activated protein kinase activation pathway...
November 14, 2016: Structure
Frédéric V Stanger, Tjaart A P de Beer, David M Dranow, Tilman Schirmer, Isabelle Phan, Christoph Dehio
The BID (Bep intracellular delivery) domain functions as secretion signal in a subfamily of protein substrates of bacterial type IV secretion (T4S) systems. It mediates transfer of (1) relaxases and the attached DNA during bacterial conjugation, and (2) numerous Bartonella effector proteins (Beps) during protein transfer into host cells infected by pathogenic Bartonella species. Furthermore, BID domains of Beps have often evolved secondary effector functions within host cells. Here, we provide crystal structures for three representative BID domains and describe a novel conserved fold characterized by a compact, antiparallel four-helix bundle topped with a hook...
November 14, 2016: Structure
Eng-Hui Yap, Andras Fiser
Members of the extracellular immunoglobulin superfamily (IgSF) play a key role in immune regulation through the control of the co-stimulatory pathway, and have emerged as potent drug targets in cancers, infectious diseases, and autoimmunity. Despite the difficult experimental access to this class of proteins, single structures of ectodomains of IgSF proteins are solved with regularity. However, the most biologically critical challenge for this class of proteins is the identification of their cognate ligands that communicate intercellular signals...
November 11, 2016: Structure
Fátima Herranz-Trillo, Minna Groenning, Andreas van Maarschalkerweerd, Romà Tauler, Bente Vestergaard, Pau Bernadó
Formation of amyloids is the hallmark of several neurodegenerative pathologies. Structural investigation of these complex transformation processes poses significant experimental challenges due to the co-existence of multiple species. The additive nature of small-angle X-ray scattering (SAXS) data allows for probing the evolution of these mixtures of oligomeric states, but the decomposition of SAXS data into species-specific spectra and relative concentrations is burdened by ambiguity. We present an objective SAXS data decomposition method by adapting the multivariate curve resolution alternating least squares (MCR-ALS) chemometric method...
November 9, 2016: Structure
Marcel Bolten, Cyrille L Delley, Marc Leibundgut, Daniel Boehringer, Nenad Ban, Eilika Weber-Ban
Mycobacterium tuberculosis harbors proteasomes that recruit substrates for degradation through an ubiquitin-like modification pathway. Recently, a non-ATPase activator termed Bpa (bacterial proteasome activator) was shown to support an alternate proteasomal degradation pathway. Here, we present the cryo-electron microscopy (cryo-EM) structure of Bpa in complex with the 20S core particle (CP). For docking into the cryo-EM density, we solved the X-ray structure of Bpa, showing that it forms tight four-helix bundles arranged into a 12-membered ring with a 40 Å wide central pore and the C-terminal helix of each protomer protruding from the ring...
November 9, 2016: Structure
Jemma L Trick, Sivapalan Chelvaniththilan, Gianni Klesse, Prafulla Aryal, E Jayne Wallace, Stephen J Tucker, Mark S P Sansom
Ion channels play key roles in cell membranes, and recent advances are yielding an increasing number of structures. However, their functional relevance is often unclear and better tools are required for their functional annotation. In sub-nanometer pores such as ion channels, hydrophobic gating has been shown to promote dewetting to produce a functionally closed (i.e., non-conductive) state. Using the serotonin receptor (5-HT3R) structure as an example, we demonstrate the use of molecular dynamics to aid the functional annotation of channel structures via simulation of the behavior of water within the pore...
November 8, 2016: Structure
Firdaus Samsudin, Maite L Ortiz-Suarez, Thomas J Piggot, Peter J Bond, Syma Khalid
The envelope of Gram-negative bacteria is highly complex, containing separate outer and inner membranes and an intervening periplasmic space encompassing a peptidoglycan (PGN) cell wall. The PGN scaffold is anchored non-covalently to the outer membrane via globular OmpA-like domains of various proteins. We report atomically detailed simulations of PGN bound to OmpA in three different states, including the isolated C-terminal domain (CTD), the full-length monomer, or the complete full-length dimeric form. Comparative analysis of dynamics of OmpA CTD from different bacteria helped to identify a conserved PGN-binding mode...
November 8, 2016: Structure
Matthew T Eddy, Tatiana Didenko, Raymond C Stevens, Kurt Wüthrich
Fluorine-19 nuclear magnetic resonance (NMR) was used to study conformational equilibria at the intracellular tips of helices VI and VII in a variant β2-adrenergic receptor (β2AR) containing T4-lysozyme fused into the third intracellular loop (β2AR-T4L), a G protein-coupled receptor (GPCR) modification widely used in crystal structure determination. G-protein signaling at helix VI showed nearly complete population of an active-like state for all ligand efficacies in the absence of an intracellular protein...
November 8, 2016: Structure
Madeleine Strickland, Ann Marie Stanley, Guangshun Wang, Istvan Botos, Charles D Schwieters, Susan K Buchanan, Alan Peterkofsky, Nico Tjandra
Paralogous enzymes arise from gene duplication events that confer a novel function, although it is unclear how cross-reaction between the original and duplicate protein interaction network is minimized. We investigated HPr:EI(sugar) and NPr:EI(Ntr), the initial complexes of paralogous phosphorylation cascades involved in sugar import and nitrogen regulation in bacteria, respectively. Although the HPr:EI(sugar) interaction has been well characterized, involving multiple complexes and transient interactions, the exact nature of the NPr:EI(Ntr) complex was unknown...
November 8, 2016: Structure
Deepankar Gahloth, Colin Levy, Graham Heaven, Flavia Stefani, Lydia Wunderley, Paul Mould, Matthew J Cliff, Jordi Bella, Alistair J Fielding, Philip Woodman, Lydia Tabernero
Endosomal sorting complexes required for transport (ESCRTs) are essential for ubiquitin-dependent degradation of mitogenic receptors, a process often compromised in cancer pathologies. Sorting of ubiquinated receptors via ESCRTs is controlled by the tumor suppressor phosphatase HD-PTP. The specific interaction between HD-PTP and the ESCRT-I subunit UBAP1 is critical for degradation of growth factor receptors and integrins. Here, we present the structural characterization by X-ray crystallography and double electron-electron resonance spectroscopy of the coiled-coil domain of HD-PTP and its complex with UBAP1...
November 8, 2016: Structure
Aaron T Bozzi, Lukas B Bane, Wilhelm A Weihofen, Abhishek Singharoy, Eduardo R Guillen, Hidde L Ploegh, Klaus Schulten, Rachelle Gaudet
The widely conserved natural resistance-associated macrophage protein (Nramp) family of divalent metal transporters enables manganese import in bacteria and dietary iron uptake in mammals. We determined the crystal structure of the Deinococcus radiodurans Nramp homolog (DraNramp) in an inward-facing apo state, including the complete transmembrane (TM) segment 1a (absent from a previous Nramp structure). Mapping our cysteine accessibility scanning results onto this structure, we identified the metal-permeation pathway in the alternate outward-open conformation...
November 8, 2016: Structure
Alexandre R Gingras, Wilma Puzon-McLaughlin, Andrey A Bobkov, Mark H Ginsberg
Ras-interacting protein 1 (Rasip1) is an endothelial-specific Rap1 and Ras effector, important for vascular development and angiogenesis. Here, we report the crystal structure of the Rasip1 RA domain (RRA) alone, revealing the basis of dimerization, and in complex with Rap1 at 2.8 Å resolution. In contrast to most RA domains, RRA formed a dimer that can bind two Rap1 (KD = 0.9 μM) or Ras (KD = 2.2 μM) molecules. We solved the Rap1-RRA complex and found that Rasip1 binds Rap1 in the Switch I region, and Rap1 binding induces few conformation changes to Rasip1 stabilizing a β strand and an unstructured loop...
November 8, 2016: Structure
Ziao Fu, Sandip Kaledhonkar, Anneli Borg, Ming Sun, Bo Chen, Robert A Grassucci, Måns Ehrenberg, Joachim Frank
Upon encountering a stop codon on mRNA, polypeptide synthesis on the ribosome is terminated by release factors, and the ribosome complex, still bound with mRNA and P-site-bound tRNA (post-termination complex, PostTC), is split into ribosomal subunits, ready for a new round of translational initiation. Separation of post-termination ribosomes into subunits, or "ribosome recycling," is promoted by the joint action of ribosome-recycling factor (RRF) and elongation factor G (EF-G) in a guanosine triphosphate (GTP) hydrolysis-dependent manner...
November 2, 2016: Structure
Chris A Brosey, Chris Ho, Winnie Z Long, Sukrit Singh, Kathryn Burnett, Greg L Hura, Jay C Nix, Gregory R Bowman, Tom Ellenberger, John A Tainer
Apoptosis-inducing factor (AIF) is critical for mitochondrial respiratory complex biogenesis and for mediating necroptotic parthanatos; these functions are seemingly regulated by enigmatic allosteric switching driven by NADH charge-transfer complex (CTC) formation. Here, we define molecular pathways linking AIF's active site to allosteric switching regions by characterizing dimer-permissive mutants using small-angle X-ray scattering (SAXS) and crystallography and by probing AIF-CTC communication networks using molecular dynamics simulations...
November 2, 2016: Structure
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