5 research outputs found
A Conformational Switch Triggers Nitrogenase Protection from Oxygen Damage by Shethna Protein II (FeSII)
The
two-component metalloprotein nitrogenase catalyzes the reductive
fixation of atmospheric dinitrogen into bioavailable ammonium in diazotrophic
prokaryotes. The process requires an efficient energy metabolism,
so that although the metal clusters of nitrogenase rapidly decompose
in the presence of dioxygen, many free-living diazotrophs are obligate
aerobes. In order to retain the functionality of the nitrogen-fixing
enzyme, some of these are able to rapidly âswitch-offâ
nitrogenase, by shifting the enzyme into an inactive but oxygen-tolerant
state. Under these conditions the two components of nitrogenase form
a stable, ternary complex with a small [2Fe:2S] ferredoxin termed
FeSII or the âShethna protein IIâ. Here we have produced
and isolated <i>Azotobacter vinelandii</i> FeS II and have
determined its three-dimensional structure to 2.1 Ă
resolution
by X-ray diffraction. In the crystals, the dimeric protein was present
in two distinct states that differ in the conformation of an extended
loop in close proximity to the ironâsulfur cluster. We show
that this rearrangement is redox-dependent and forms the molecular
basis for oxygen-dependent conformational protection of nitrogenase.
Protection assays highlight that FeSII binds to a preformed complex
of MoFe and Fe protein upon activation, primarily through electrostatic
interactions. The surface properties and known complexes of nitrogenase
component proteins allow us to propose a model of the conformationally
protected ternary complex of nitrogenase
Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A StructureâActivity Relationship Study
Sirtuins are NAD<sup>+</sup>-dependent
protein deacylases that
cleave off acetyl but also other acyl groups from the Îľ-amino
group of lysines in histones and other substrate proteins. Dysregulation
of human Sirt2 (hSirt2) activity has been associated with the pathogenesis
of cancer, inflammation, and neurodegeneration, which makes the modulation
of hSirt2 activity a promising strategy for pharmaceutical intervention.
The sirtuin rearranging ligands (SirReals) have recently been discovered
by us as highly potent and isotype-selective hSirt2 inhibitors. Here,
we present a well-defined structureâactivity relationship study,
which rationalizes the unique features of the SirReals and probes
the limits of modifications on this scaffold regarding inhibitor potency.
Moreover, we present a crystal structure of hSirt2 in complex with
an optimized SirReal derivative that exhibits an improved in vitro
activity. Lastly, we show cellular hyperacetylation of the hSirt2
targeted tubulin caused by our improved lead structure
Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4â[4-(2-Adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)
Inhibition of 11β-HSD1 is viewed as a potential
target for
the treatment of obesity and other elements of the metabolic syndrome.
We report here the optimization of a carboxylic acid class of inhibitors
from AZD4017 (<b>1</b>) to the development candidate AZD8329
(<b>27</b>). A structural change from pyridine to pyrazole together
with structural optimization led to an improved technical profile
in terms of both solubility and pharmacokinetics. The extent of acyl
glucuronidation was reduced through structural optimization of both
the carboxylic acid and amide substituents, coupled with a reduction
in lipophilicity leading to an overall increase in metabolic stability
Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)
Inhibition of 11β-HSD1 is an attractive mechanism
for the
treatment of obesity and other elements of the metabolic syndrome.
We report here the discovery of a nicotinic amide derived carboxylic
acid class of inhibitors that has good potency, selectivity, and pharmacokinetic
characteristics. Compound <b>11i</b> (AZD4017) is an effective
inhibitor of 11β-HSD1 in human adipocytes and exhibits good
druglike properties and as a consequence was selected for clinical
development