Biochemistry publications (MU)
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Items in this collection are the scholarly output of the Division of Biochemistry faculty, staff, and students, either alone or as co-authors, and which may or may not have been published in an alternate format. Items may contain more than one file type.
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Item Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR(eLife Sciences Publications Ltd, 2019) Meyer, N. L.; Hu, G.; Davulcu, O.; Xie, Q.; Noble, A. J.; Yoshioka, C.; Gingerich, D. S.; Trzynka, A.; David, L.; Stagg, S. M.; Chapman, M. S.; BiochemistryAdeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 A degrees resolution. AAVR binds between AAV's spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR's footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.Item Synthesis, Derivatization, and Structural Analysis of Phosphorylated Mono-, Di-, and Trifluorinated d -Gluco-heptuloses by Glucokinase: Tunable Phosphoglucomutase Inhibition(American Chemical Society, 2019) Zhu, J. -S.; Stiers, K. M.; Winter, S. M.; Garcia, A. D.; Versini, A. F.; Beamer, Lesa J. (Lesa Jean); Jakeman, D. L.; BiochemistryGlucokinase phosphorylated a series of C-1 fluorinated [alpha]-d-gluco-heptuloses. These phosphorylated products were discovered to be inhibitors of [alpha]-phosphomannomutase/phosphoglucomutase ([alpha]PMM/PGM) and [beta]-phosphoglucomutase ([beta]PGM). Inhibition potency with both mutases inversely correlated to the degree of fluorination. Structural analysis with [alpha]PMM demonstrated the inhibitor binding to the active site, with the phosphate in the phosphate binding site and the anomeric hydroxyl directed to the catalytic site.Item Structural and dynamical description of the enzymatic reaction of a phosphohexomutase(American Crystallographic Association, 2019) Stiers, K. M.; Graham, A. C.; Zhu, J. -S.; Jakeman, D. L.; Nix, J. C.; Beamer, Lesa J. (Lesa Jean); BiochemistryEnzymes are known to adopt various conformations at different points along their catalytic cycles. Here, we present a comprehensive analysis of 15 isomorphous, high resolution crystal structures of the enzyme phosphoglucomutase from the bacterium Xanthomonas citri. The protein was captured in distinct states critical to function, including enzyme-substrate, enzyme-product, and enzyme-intermediate complexes. Key residues in ligand recognition and regions undergoing conformational change are identified and correlated with the various steps of the catalytic reaction. In addition, we use principal component analysis to examine various subsets of these structures with two goals: (1) identifying sites of conformational heterogeneity through a comparison of room temperature and cryogenic structures of the apo-enzyme and (2) a priori clustering of the enzyme-ligand complexes into functionally related groups, showing sensitivity of this method to structural features difficult to detect by traditional methods. This study captures, in a single system, the structural basis of diverse substrate recognition, the subtle impact of covalent modification, and the role of ligand-induced conformational change in this representative enzyme of the [alpha]-D-phosphohexomutase superfamily.Item Supplemental data for 3,3'-diindolylmethane inhibits advanced prostate cancer in the TRAMP mouse model(2018) Li, Yufei; Mahloch, Nathaniel W.; Starkey, Nicholas J.E.; Peña-Luna, Monica; Rottinghaus, George E.; Fritsche, Kevin L., 1958-; Besch-Williford, Cynthia; Lubahn, Dennis B.