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GAF domains regulate the catalytic activity of certain vertebrate cyclic nucleotide phosphodiesterases (PDEs) by allosteric, noncatalytic binding of cyclic nucleotides. GAF domains arranged in tandem are found in PDE2, −5, −6, −10, and −11, all of which regulate the cellular concentrations of the second messengers cAMP and/or cGMP. Nucleotide binding to GAF domains affects the overall conformation...
Lincosamides make up an important class of antibiotics used against a wide range of pathogens, including methicillin-resistant Staphylococcus aureus. Predictably, lincosamide-resistant microorganisms have emerged with antibiotic modification as one of their major resistance strategies. Inactivating enzymes LinB/A catalyze adenylylation of the drug; however, little is known about their mechanistic...
The discoidin domain receptors, DDR1 and DDR2, are widely expressed receptor tyrosine kinases that are activated by triple-helical collagen. They control important aspects of cell behavior and are dysregulated in several human diseases. The major DDR2-binding site in collagens I–III is a GVMGFO motif (O is hydroxyproline) that also binds the matricellular protein SPARC. We have determined the crystal...
Human coagulation factor IX serves both to maintain and to control blood coagulation. The dual function of this hemophilic factor is implemented by a tiered activation mechanism. Processed two-chain factor IXa is catalytically silent; only together with its cofactor VIIIa does factor IXa form the highly potent Xase complex. The detailed mechanism of this secondary activation has remained elusive so...
The reference-free averaging of three-dimensional electron microscopy (3D-EM) reconstructions with empty regions in Fourier space represents a pressing problem in electron tomography and single-particle analysis. We present a maximum likelihood algorithm for the simultaneous alignment and classification of subtomograms or random conical tilt (RCT) reconstructions, where the Fourier components in the...
Experimental observation has led to the commonly held view that native state protein topology is the principle determinant of mechanical strength. However, the PKD domains of polycystin-1 challenge this assumption: they are stronger than predicted from their native structure. Molecular dynamics simulations suggest that force induces rearrangement to an intermediate structure, with nonnative hydrogen...
Novel inhibitors are needed to counteract the rapid emergence of drug-resistant HIV variants. HIV-1 reverse transcriptase (RT) has both DNA polymerase and RNase H (RNH) enzymatic activities, but approved drugs that inhibit RT target the polymerase. Inhibitors that act against new targets, such as RNH, should be effective against all of the current drug-resistant variants. Here, we present 2.80 Å and...
The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling ∼3 μs) of the A2A receptor in cholesterol-free bilayers, with and without the antagonist ZM241385 bound, demonstrate the instability of helix II in the apo receptor in cholesterol-poor membrane regions. We directly observe that the effect of cholesterol...
In this issue of Structure, Taylor et al. (2009) present the most complete model of an eukaryotic ribosome to date. This achievement represents a critical milestone along the path to structurally defining the unique aspects of the eukaryotic protein synthetic machinery.
Recent structural studies have outlined the mechanism of protease inhibition by active site-directed antibodies. However, the molecular basis of allosteric inhibition by antibodies has been elusive. Here we report the 2.35 Å resolution structure of the trypsin-like serine protease hepatocyte growth factor activator (HGFA) in complex with the allosteric antibody Ab40, a potent inhibitor of HGFA catalytic...
Many three-dimensional density maps of 70S ribosome at various functional states are available now in the Electron Microscopy DataBank at EBI. We used our new flexible-fitting approach to systematically analyze these maps to reveal the global conformational differences between the EM structures. Large-scale ratchet-like deformations were observed in an EM structure of the initiation complex and in...
Despite the emergence of a large number of X-ray crystallographic models of the bacterial 70S ribosome over the past decade, an accurate atomic model of the eukaryotic 80S ribosome is still not available. Eukaryotic ribosomes possess more ribosomal proteins and ribosomal RNA than do bacterial ribosomes, which are implicated in extraribosomal functions in the eukaryotic cells. By combining cryo-EM...
This year's Nobel Prize in Chemistry celebrates a multitude of research areas, making the difficult selection of those most responsible for providing atomic details of the nanomachine that makes proteins according to genetic instructions. The Ribosome and RNA polymerase (recognized in 2006) structures highlight a puzzling asymmetry at the origins of biology.
Drug-resistant mutations (DRMs) in HIV-1 protease are a major challenge to antiretroviral therapy. Protease-substrate interactions that are determined to be critical for native selectivity could serve as robust targets for drug design that are immune to DRMs. In order to identify the structural mechanisms of selectivity, we developed a peptide-docking algorithm to predict the atomic structure of protease-substrate...
Bacteria utilize multiple strategies to circumvent antibiotics, producing broad specificity exporters or enzymes that catalyze the modification of either antibiotics or their targets. A report in this issue of Structure provides the structural and catalytic mechanisms of LinB, an adenylyltransferase of E. faecium that confers resistance to the lincosamide antibiotic clindamycin.
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