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  • 1
    Language: English
    In: Biochemistry, 16 October 2018, Vol.57(41), pp.5925-5929
    Description: Computational simulations of electrostatic potentials (ESPs), based on atomistic models and independent atomic scattering factors, have remained challenging when applied to the oxygen-evolving complex (OEC) of photosystem II (PSII). Here, we overcome that challenge by using an ESP function obtained with density functional theory and atomic coordinates for the OEC of PSII obtained by optimization of the dark-adapted S state. We find that the ESP is much higher for the OEC than for the nearby reference side chain of amino acid residue D1-H190. In contrast, experimental ESP maps recently published for two PSII-light-harvesting complex II super-complexes show that the ESP of the OEC is approximately half the value of the D1-H190 side chain. The apparent disparity is attributed to a reduced 31-38% occupancy of the OEC, likely associated with its reduction by electron scattering.
    Keywords: Models, Molecular ; Photosystem II Protein Complex -- Chemistry ; Thylakoids -- Chemistry
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 October 2018, Vol.115(43), pp.E10022-E10031
    Description: SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.
    Keywords: Samhd1 ; Allosteric Regulation ; Dntpase ; Nucleotide Analog Drugs ; Substrate Selection ; Allosteric Site -- Drug Effects ; Catalytic Domain -- Drug Effects ; Drug Interactions -- Physiology ; Leukemia, Myeloid, Acute -- Metabolism ; SAM Domain and HD Domain-Containing Protein 1 -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Biochemistry, 12 March 2019, Vol.58(10), pp.1379-1387
    Description: In photosystem II (PSII), photosynthetic water oxidation occurs at the tetramanganese-calcium cluster that cycles through light-induced intermediates (S-S) to produce oxygen from two substrate waters. The surrounding hydrogen-bonded amino acid residues and waters form channels that facilitate proton transfer and substrate water delivery, thereby ensuring efficient water oxidation. The residue D1-S169 lies in the "narrow" channel and forms hydrogen bonds with the MnCaO cluster via waters W1 and Wx. To probe the role of the narrow channel in substrate-water binding, we studied the D1-S169A mutation. PSII core complexes isolated from mutant cells exhibit inefficient S-state cycling and delayed oxygen evolution. The S-state multiline EPR spectrum of D1-S169A PSII core complexes differed significantly from that of wild-type, and FTIR difference spectra showed that the mutation strongly perturbs the extensive network of hydrogen bonds that extends at least from D1-Y161 (Y) to D1-D61. These results imply a possible role of D1-S169 in proton egress or substrate water delivery.
    Keywords: Chemistry ; Anatomy & Physiology;
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 4
    Language: English
    In: Inorganics, 01 March 2019, Vol.7(3), p.39
    Description: The influence of the environment on the functionality of the oxygen-evolving complex (OEC) of photosystem II has long been a subject of great interest. In particular, various water channels, which could serve as pathways for substrate water diffusion, or proton translocation, are thought to be critical to catalytic performance of the OEC. Here, we address the dynamical nature of hydrogen bonding along the water channels by performing molecular dynamics (MD) simulations of the OEC and its surrounding protein environment in the S1 and S2 states. Through the eigenvector centrality (EC) analysis, we are able to determine the characteristics of the water network and assign potential functions to the major channels, namely that the narrow and broad channels are likely candidates for proton/water transport, while the large channel may serve as a path for larger ions such as chloride and manganese thought to be essential during PSII assembly.
    Keywords: Oxygen-Evolving Complex ; Community Network Analysis ; Water Channels ; Chemistry
    E-ISSN: 2304-6740
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  • 5
    Language: English
    In: Cellular and molecular life sciences : CMLS, 21 August 2019
    Description: Sulfur-containing compounds within a physiological relevant, natural odor space, such as the key food odorants, typically constitute the group of volatiles with the lowest odor thresholds. The observation that certain metals, such as copper, potentiate the smell of sulfur-containing, metal-coordinating odorants led to the hypothesis that their cognate receptors are metalloproteins. However, experimental evidence is sparse-so far, only one human odorant receptor, OR2T11, and a few mouse receptors, have been reported to be activated by sulfur-containing odorants in a copper-dependent way, while the activation of other receptors by sulfur-containing odorants did not depend on the presence of metals. Here we identified an evolutionary conserved putative copper interaction motif CC/CSSH, comprising two copper-binding sites in TMH5 and TMH6, together with the binding pocket for 3-mercapto-2-methylpentan-1-ol in the narrowly tuned human receptor OR2M3. To characterize the copper-binding motif, we combined homology modeling, docking studies, site-directed mutagenesis, and functional expression of recombinant ORs in a cell-based, real-time luminescence assay. Ligand activation of OR2M3 was potentiated in the presence of copper. This effect of copper was mimicked by ionic and colloidal silver. In two broadly tuned receptors, OR1A1 and OR2W1, which did not reveal a putative copper interaction motif, activation by their most potent, sulfur-containing key food odorants did not depend on the presence of copper. Our results suggest a highly conserved putative copper-binding motif to be necessary for a copper-modulated and thiol-specific function of members from three subfamilies of family 2 ORs.
    Keywords: Copper-Binding Motif ; Gpcr ; Molecular Modeling ; Silver Ions ; Structure–Function Study
    ISSN: 1420682X
    E-ISSN: 1420-9071
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: Photosynthesis research, September 2019, Vol.141(3), pp.331-341
    Description: The oxidation of water to O is catalyzed by the Oxygen Evolving Complex (OEC), a MnCaO complex in Photosystem II (PSII). The OEC is sequentially oxidized from state S to S. The S state, (Mn)(Mn), coexists in two redox isomers: S, where Mn4 is Mn and S, where Mn1 is Mn. Mn4 has two terminal water ligands, whose proton affinity is affected by the Mn oxidation state. The relative energy of the two S redox isomers and the protonation state of the terminal water ligands are analyzed using classical multi-conformer continuum electrostatics (MCCE). The Monte Carlo simulations are done on QM/MM optimized S and S structures docked back into the complete PSII, keeping the protonation state of the protein at equilibrium with the OEC redox and protonation states. Wild-type PSII, chloride-depleted PSII, PSII in the presence of oxidized Y/protonated D1-H190, and the PSII mutants D2-K317A, D1-D61A, and D1-S169A are studied at pH 6. The wild-type PSII at pH 8 is also described. In qualitative agreement with experiment, in wild-type PSII, the S redox isomer is the lower energy state; while chloride depletion or pH 8 stabilizes the S state and the mutants D2-K317A, D1-D61A, and D1-S169A favor the S state. The protonation states of D1-E329, D1-E65, D1-H337, D1-D61, and the terminal waters on Mn4 (W1 and W2) are affected by the OEC oxidation state. The terminal W2 on Mn4 is a mixture of water and hydroxyl in the S state, indicating the two water protonation states have similar energy, while it remains neutral in the S and S states. In wild-type PSII, advancement to S leads to negligible proton loss and so there is an accumulation of positive charge. In the analyzed mutations and Cl depleted PSII, additional deprotonation is found upon formation of S state.
    Keywords: Grand Canonical Monte Carlo Simulations ; Linear Response Approximation (Lra) ; Oxygen Evolving Complex (Oec) ; Photosystem II ; Proton Transfer ; Pka
    ISSN: 01668595
    E-ISSN: 1573-5079
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