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  • 1
    Language: English
    In: Biochemistry, 11 March 2014, Vol.53(9), pp.1466-76
    Description: The binding of the TRIM5α restriction factor to the HIV capsid is mediated by the C-terminal SPRY domain of TRIM5α. Atomic-level details of this host-pathogen interaction, which involves mobile variable loops of the SPRY domain, remain unclear. Some of the key determinants of restriction are encompassed by the long and disordered v1 loop of the SPRY domain. We applied molecular modeling to elucidate the conformational repertoire of the v1 loop and its role in the interaction with the capsid. All-atom replica exchange molecular dynamics revealed multiple transient, interconverting states of the v1 loop consistent with the intrinsic disorder observed experimentally. The docking of the SPRY conformations representing 10 most populated states onto the high-resolution model of the assembled HIV-1 capsid revealed that a subset of v1 conformations produced plausible binding poses, in which the SPRY domain binds close to the pseudo-2-fold symmetry axis and the v1 loop spans the interhexamer gap. Such binding mode is well supported by the NMR binding data and known escape mutants. We speculate that the binding mode that involves interaction of the capsid with a subset of preexisting SPRY conformations arising from the intrinsic disorder of the v1 loop may explain the remarkable ability of TRIM5α to resist viral evasion by mutagenesis and to restrict divergent retroviruses.
    Keywords: Capsid -- Metabolism ; Carrier Proteins -- Chemistry ; HIV-1 -- Metabolism
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 2
    Language: English
    In: Biophysical Journal, 28 January 2014, Vol.106(2), pp.61a-61a
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
    Source: ScienceDirect Journals (Elsevier)
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 August 2012, Vol.109(33), pp.13278-83
    Description: Tripartite motif protein TRIM5α blocks retroviral replication after cell entry, and species-specific differences in its activity are determined by sequence variations within the C-terminal B30.2/PRYSPRY domain. Here we report a high-resolution structure of a TRIM5α PRYSPRY domain, the PRYSPRY of the rhesus monkey TRIM5α that potently restricts HIV infection, and identify features involved in its interaction with the HIV capsid. The extensive capsid-binding interface maps on the structurally divergent face of the protein formed by hypervariable loop segments, confirming that TRIM5α evolution is largely determined by its binding specificity. Interactions with the capsid are mediated by flexible variable loops via a mechanism that parallels antigen recognition by IgM antibodies, a similarity that may help explain some of the unusual functional properties of TRIM5α. Distinctive features of this pathogen-recognition interface, such as structural plasticity conferred by the mobile v1 segment and interaction with multiple epitopes, may allow restriction of divergent retroviruses and increase resistance to capsid mutations.
    Keywords: Capsid -- Chemistry ; HIV-1 -- Chemistry ; Macaca Mulatta -- Metabolism ; Proteins -- Chemistry
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: Physical Review B, 6/2011, Vol.83(23)
    Description: We propose a new quantum model interpolating between the fully frustrated spin-1/2 Ising model in a transverse field and a dimer model. This model contains a resonating-valence-bond phase, including a line with an exactly solvable ground state of the Rokhsar-Kivelson type. We discuss the phase diagrams of this model on the square and triangular (in terms of the dimer representation) lattices. Comment: 9 pages, 7 figures
    Keywords: Condensed Matter - Strongly Correlated Electrons;
    ISSN: 1098-0121
    E-ISSN: 1550-235X
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  • 5
    Language: English
    In: Physical Review B, 1/2013, Vol.87(2)
    Description: We study a diffusive superconductor - normal metal - superconductor (SNS) junction in an external magnetic field. In the limit of a long junction, we find that the form of the dependence of the Josephson current on the field and on the length of the junction depends on the ratio between the junction width and the length associated with the magnetic field. A certain critical ratio between these two length scales separates two different regimes. In narrow junctions, the critical current exhibits a pure decay as a function of the junction length or of the magnetic field. In wide junctions, the critical current exhibits damped oscillations as a function of the same parameters. This damped oscillating behavior differs from the Fraunhofer pattern typical for short or tunnel junctions. In wide and long junctions, superconducting pair correlations and supercurrent are localized along the edges of the junction. Comment: 9 pages, 4 figures, minor modifications corresponding to the published version
    Keywords: Condensed Matter - Superconductivity ; Condensed Matter - Mesoscale And Nanoscale Physics;
    ISSN: 1098-0121
    E-ISSN: 1550-235X
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(9), p.e0138780
    Description: The human antigen R (HuR) stabilizes many mRNAs of proto-oncogene, transcription factors, cytokines and growth factors by recognizing AU-rich elements (AREs) presented in their 3' or 5' untranslated region (UTR). Multiple lines of experimental evidence suggest that this process plays a key...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Physical review. E, Statistical, nonlinear, and soft matter physics, February 2013, Vol.87(2), pp.022114
    Description: We propose to describe correlations in classical and quantum systems in terms of full counting statistics of a suitably chosen discrete observable. The method is illustrated with two exactly solvable examples: the classical one-dimensional Ising model and the quantum spin-1/2 XY chain. For the one-dimensional Ising model, our method results in a phase diagram with two phases distinguishable by the long-distance behavior of the Jordan-Wigner strings. For the anisotropic spin-1/2 XY chain in a transverse magnetic field, we compute the full counting statistics of the magnetization and use it to classify quantum phases of the chain. The method, in this case, reproduces the previously known phase diagram. We also discuss the relation between our approach and the Lee-Yang theory of zeros of the partition function.
    Keywords: Algorithms ; Magnetic Fields ; Models, Statistical
    E-ISSN: 1550-2376
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 30 December 2014, Vol.111(52), pp.18625-30
    Description: Upon infection of susceptible cells by HIV-1, the conical capsid formed by ∼250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. The capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host-virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the C-terminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD-CTD interface is critical for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD-CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD-CTD interface is a specific molecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus.
    Keywords: HIV-1 Ca Protein ; X-Ray Crystallography ; Drug Discovery ; Fluorescence Polarization ; Isothermal Calorimetry ; Capsid -- Chemistry ; HIV-1 -- Chemistry ; Indoles -- Chemistry ; Phenylalanine -- Analogs & Derivatives ; Mrna Cleavage and Polyadenylation Factors -- Chemistry
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: Journal of Biological Chemistry, 08/26/2016, p.jbc.C116.751446
    Description: SAMHD1 is a dNTP hydrolase, whose activity is required for maintaining low dNTP concentrations in non-cycling T cells, dendritic cells, and macrophages. SAMHD1-dependent dNTP depletion is thought to impair retroviral replication in these cells, but the relationship between the dNTPase activity and retroviral restriction is not fully understood. In this study, we investigate allosteric activation of SAMHD1 by deoxynucleotide-dependent tetramerization and measure how the lifetime of the enzymatically active tetramer is affected by different dNTP ligands bound in the allosteric site. The EC50dNTP values for SAMHD1 activation by dNTPs are in the 2-20 μm range, and the half-life of the assembled tetramer after deoxynucleotide depletion varies from minutes to hours depending on what dNTP is bound in the A2 allosteric site. Comparison of the wild-type SAMHD1 and the T592D mutant reveals that the phosphomimetic mutation affects the rates of tetramer dissociation, but has no effect on the equilibrium of allosteric activation by deoxynucleotides. Collectively, our data suggest that deoxynucleotide-dependent tetramerization contributes to regulation of deoxynucleotide levels in cycling cells, whereas in non-cycling cells restrictive to retroviral replication, SAMHD1 activation is likely to be achieved through a distinct mechanism.
    Keywords: Chemistry ; Anatomy & Physiology;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: CrossRef
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  • 10
    Language: English
    In: Journal of Molecular Biology, Dec 13, 2013, Vol.425(24), p.5032(13)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jmb.2013.07.025 Byline: Nikolaos Biris, Andrei Tomashevski, Akash Bhattacharya, Felipe Diaz-Griffero, Dmitri N. Ivanov Abstract: The restriction factor TRIM5[alpha] binds to the capsid protein of the retroviral core and blocks retroviral replication. The affinity of TRIM5[alpha] for the capsid is a major host tropism determinant of HIV and other primate immunodeficiency viruses, but the molecular interface involved in this host-pathogen interaction remains poorly characterized. Here we use NMR spectroscopy to investigate binding of the rhesus TRIM5[alpha] SPRY domain to a selection of HIV capsid constructs. The data are consistent with a model in which one SPRY domain interacts with more than one capsid monomer within the assembled retroviral core. The highly mobile SPRY v1 loop appears to span the gap between neighboring capsid hexamers making interhexamer contacts critical for restriction. The interaction interface is extensive, involves mobile loops and multiple epitopes, and lacks interaction hot spots. These properties, which may enhance resistance of TRIM5[alpha] to capsid mutations, result in relatively low affinity of the individual SPRY domains for the capsid, and the TRIM5[alpha]-mediated restriction depends on the avidity effect arising from the oligomerization of TRIM5[alpha]. Article History: Received 10 April 2013; Revised 11 July 2013; Accepted 12 July 2013 Article Note: (miscellaneous) Edited by E. Freed and M. Gale
    Keywords: Antigenic Determinants -- Analysis ; Virus Diseases -- Analysis ; Oligomers -- Analysis ; Protein Binding -- Analysis ; Monkeys -- Analysis ; Nuclear Magnetic Resonance Spectroscopy -- Analysis
    ISSN: 0022-2836
    Source: Cengage Learning, Inc.
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