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Lactate racemase is a nickel-dependent enzyme activated by a widespread maturation system
Lactate racemase is an enzyme that interconverts the L and D isomers of the common metabolite lactate. Here, the authors show that lactate racemase represents a new type of nickel-dependent enzyme, which is activated by accessory proteins that are widespread among prokaryotic microbes.
- Benoît Desguin
- , Philippe Goffin
- & Pascal Hols
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Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases
Studies have identified that mutations to metabolic enzymes can lead to abnormal biological activity and disease. Here, the authors show that in addition to this, non-enzymatic chemistry could also influence abnormal metabolic processes and disease development.
- Hanna Tarhonskaya
- , Anna M. Rydzik
- & Christopher J. Schofield
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A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
Allosteric sites are an increasingly used target for drug design. Here, the authors computationally predict an allosteric site in cathepsin K and subsequently identify a small-molecule allosteric modifier.
- Marko Novinec
- , Matevž Korenč
- & Antonio Baici
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Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer
Vitamin K epoxide reductase (VKOR) catalyses the formation of protein disulphide bonds and is the pharmacological target of the anticoagulant drug warfarin. Liu et al. present crystal structures of a bacterial VKOR in two different conformations and reveal how motions of a helix ensure unidirectional electron transfer.
- Shixuan Liu
- , Wei Cheng
- & Weikai Li
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Unexpected reactivity and mechanism of carboxamide activation in bacterial N-linked protein glycosylation
Oligosaccharyltransferases catalyse the transfer of lipid-anchored glycans onto acceptor asparagine residues in substrate proteins. By assaying chemically modified peptide substrate analogues, Lizak et al. rule out all but one of the currently postulated catalytic mechanisms for this enzyme.
- Christian Lizak
- , Sabina Gerber
- & Kaspar P. Locher
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Crystal structure of human tyrosylprotein sulfotransferase-2 reveals the mechanism of protein tyrosine sulfation reaction
The post-translational protein modification tyrosine sulfation is catalysed by tyrosylprotein sulfotransferase (TPST). Teramoto et al. present the first crystal structure of the human TPST isoform 2 complexed with a substrate peptide derived from complement C4 and 3′phosphoadenosine-5′-phosphate, revealing the molecular basis of catalysis.
- Takamasa Teramoto
- , Yukari Fujikawa
- & Yoshimitsu Kakuta
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Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors
New influenza neuramidase inhibitors may increase preparedness against influenza outbreaks. Vavricka et al.confirm the catalytic mechanism of neuramidase and show that it can be inhibited irreversibly with covalent inhibitors.
- Christopher J. Vavricka
- , Yue Liu
- & George F. Gao
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| Open AccessSupporting conditional mouse mutagenesis with a comprehensive cre characterization resource
The cre-loxP system is widely used for the generation of conditional gene knockouts. Here Heffner et al.systematically characterize cre recombinase activity in tissues of embryonic and adult cre-driver mouse strains and provide an online resource for scientists.
- Caleb S. Heffner
- , C. Herbert Pratt
- & Stephen A. Murray
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Spectroscopic observation of iodosylarene metalloporphyrin adducts and manganese(V)-oxo porphyrin species in a cytochrome P450 analogue
Metalloporphyrin compounds are studied as models of cytochrome P450, which is capable of catalysing oxidative reactions. Here, reaction conditions are varied to allow spectroscopic observation of oxidant-metalloporphyrin adducts and metal-oxo intermediates, which may elucidate reaction mechanisms.
- Mian Guo
- , Hang Dong
- & Aiwen Lei
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Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase
Poly(ADP-ribose) glycohydrolase catabolises poly(ADP-ribose), which is covalently attached to proteins following post-translational modification. In this study, the structure of poly(ADP-ribose) glycohydrolase fromTetrahymena thermophilais reported in complex with the small molecule inhibitor RBPI-3.
- Mark S. Dunstan
- , Eva Barkauskaite
- & Ivan Ahel
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Casein kinase 2 reverses tail-independent inactivation of kinesin-1
Kinesin-1 is a motor protein that transports cargo along microtubules and defects in this process can result in neurodegeneration. In this study, a role for casein kinase 2 in regulating the activity of Kinesin-1 is reported, suggesting that signalling molecules can modulate this transport process.
- Jing Xu
- , Babu J. N. Reddy
- & Steven P. Gross
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| Open AccessSubstrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site
γ-Secretase modulators have promise in the treatment of Alzheimer's disease, but their molecular target is uncertain. Here, fluorescence resonance energy transfer is used to determine that the γ-secretase allosteric site is within the γ-secretase complex and that substrate docking is required for modulators to access the site.
- Kengo Uemura
- , Katherine C. Farner
- & Oksana Berezovska
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Overlap between folding and functional energy landscapes for adenylate kinase conformational change
Enzyme function is often dependent on fluctuations between inactive and active states. Olsson and Wolf-Watz show that switching between the inactive and active states of adenylate kinase is associated with partial unfolding/refolding of the enzyme.
- Ulrika Olsson
- & Magnus Wolf-Watz
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| Open AccessDrug export and allosteric coupling in a multidrug transporter revealed by molecular simulations
The drug transporter AcrB is a component of the tripartite efflux system AcrB–AcrA–TolC, which is important in multidrug-resistantEscherichia coli. Takada and co-workers used molecular simulations to further reveal the mechanism of drug export.
- Xin-Qiu Yao
- , Hiroo Kenzaki
- & Shoji Takada