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Ionotropic glutamate receptors are ligand-gated transmembrane ion channels activated by the binding of glutamate. The free energy landscapes governing the opening/closing of the GluR2 S1S2 ligand-binding domain in the apo, DNQX-, and glutamate-bound forms are computed by using all-atom molecular dynamics simulations with explicit solvent, in conjunction with an umbrella sampling strategy. The apo...
Feast/famine regulatory proteins (FFRPs) comprise the largest group of archaeal transcription factors. Crystal structures of an FFRP, DM1 from Pyrococcus, were determined in complex with isoleucine, which increases the association state of DM1 to form octamers, and with selenomethionine, which decreases it to maintain dimers under some conditions. Asp39 and Thr/Ser at 69–71 were identified as being...
The WD40-repeat protein Cia1 is an essential, conserved member of the cytosolic iron-sulfur (Fe/S) protein assembly (CIA) machinery in eukaryotes. Here, we report the crystal structure of Saccharomyces cerevisiae Cia1 to 1.7 Å resolution. The structure folds into a β propeller with seven blades pseudo symmetrically arranged around a central axis. Structure-based sequence alignment of Cia1 proteins...
The multidomain zinc endopeptidase matrix metalloproteinase-9 (MMP-9) is a recognized therapeutic target in autoimmune diseases, vascular pathologies, and cancer. Despite its importance, structural characterization of full-length pro-MMP-9 is incomplete. Here, we report the structural model of full-length pro-MMP-9 and, in particular, the molecular character of its unique proline-rich and heavily...
The AMP-activated protein kinase (AMPK), a sensor of cellular energy status found in all eukaryotes, responds to changes in intracellular adenosine nucleotide levels resulting from metabolic stresses. Here we describe crystal structures of a heterotrimeric regulatory core fragment from Schizosaccharomyces pombe AMPK in complex with ADP, ADP/AMP, ADP/ATP, and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranotide...
The WD-repeat domain is a highly conserved recognition module in eukaryotes involved in diverse cellular processes. It is still not well understood how the bottom of a WD-repeat domain recognizes its binding partners. The WD-repeat-containing protein EED is one component of the PRC2 complex that possesses histone methyltransferase activity required for gene repression. Here we report the crystal structure...
In this issue of Structure, Jin et al. (2007) report the structure of Schizosaccharomyces pombe AMPK embracing two moles of ADP by its γ subunit. This structure highlights the complexity of AMPK regulation across eukaryotes and challenges the regulatory dogma.
Binding to helix 12 of the ligand-binding domain of PPARγ is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPARγ with agonists that induced graded transcriptional responses. Here we present crystal...
RNA polymerases (Pol) II and III synthesize eukaryotic mRNAs and tRNAs, respectively. The crystal structure of the 12 subunit Pol II is known, but only limited structural information is available for the 17 subunit Pol III. Using mass spectrometry (MS), we correlated masses of Pol II complexes with the Pol II structure. Analysis of Pol III showed that the complete enzyme contains a single copy of...
AAA+ proteases are frequently regulated by adaptors that modulate spatial and temporal control of protein turnover. Caulobacter crescentus is an α-proteobacterium which requires protein degradation by the AAA+ ClpXP protease for cell-cycle progression, and contains an adaptor (SspBα) that binds ssrA-tagged proteins and targets them to ClpXP. Here we determine the tag-binding specificity and crystal...
The ultraviolet damage endonuclease (UVDE) performs the initial step in an alternative excision repair pathway of UV-induced DNA damage, nicking immediately adjacent to the 5′ phosphate of the damaged nucleotides. Unique for a single-protein DNA repair endonuclease, it can detect different types of damage. Here we show that Thermus thermophilus UVDE shares some essential structural features with Endo...
Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Analytical ultracentrifugation (AUC) and crystallographic analysis showed that ASK1 forms a tight dimer (K d ∼ 0.2 μM) interacting in a head-to-tail...
In this issue of Structure, the high-resolution structure of the ultraviolet damage endonuclease by Paspaleva et al. (2007) provides the first glimpse at a third DNA repair mechanism that efficiently repairs UV-induced DNA damage. The surprising structural homology to Endonuclease IV suggests a path for DNA binding and provides insights into DNA hydrolysis.
Numerous vesiculation processes throughout the eukaryotic cell are dependent on the protein dynamin, a large GTPase that constricts lipid bilayers. We have combined X-ray crystallography and cryo-electron microscopy (cryo-EM) data to generate a coherent model of dynamin-mediated membrane constriction. GTPase and pleckstrin homology domains of dynamin were fit to cryo-EM structures of human dynamin...
B. stearothermophilus tryptophanyl-tRNA synthetase catalysis proceeds via high-energy protein conformations. Unliganded MD trajectories of the pretransition-state complex with Mg 2+ •ATP and the (post) transition-state analog complex with adenosine tetraphosphate relax rapidly in opposite directions, the former regressing, the latter progressing along the structural reaction coordinate. The...
The coexistence of multiple distinct structural states often obstructs the application of three-dimensional cryo-electron microscopy to large macromolecular complexes. Maximum likelihood approaches are emerging as robust tools for solving the image classification problems that are posed by such samples. Here, we propose a statistical data model that allows for a description of the experimental image...
Proteases face a daunting task in tackling the huge variety of protein folds. In this issue of Structure, Irit Sagi's laboratory exploits atomic force microscopy and SAXS to reveal the extreme flexibility of matrix metalloproteinase (MMP)-9, heralding new functional possibilities for MMPs (Rosenblum et al., 2007).
The molecular dynamics simulation of the binding domain of a glutamate receptor presented in this issue of Structure (Lau & Roux, 2007) provides insights into large-scale fluctuations of this protein that are supported by experiment and provide constraints on possible models for the function of the intact glutamate receptor.
A previously introduced kinetic-rate constant (k/k 0 ) method, where k and k 0 are the folding (unfolding) rate constants in the mutant and the wild-type forms, respectively, of a protein, has been applied to obtain qualitative information about structure in the transition state ensemble (TSE) of bovine pancreatic ribonuclease A (RNase A), which contains four native disulfide bonds...
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