Disordered protein regions partner up the cBAF remodeler for a chromatin dance.

Intrinsically disordered protein regions form condensates and mediate interactions with factors that regulate gene activity. Patil et al. decode how such regions within the chromatin remodeler cBAF choreograph self-condensation and non-self interactions with transcriptional regulators, potentially impacting disease.

An Inhibitor-in-Pieces Approach to DAHP Synthase Inhibition: Potent Enzyme and Bacterial Growth Inhibition.

3-Deoxy-d-heptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate biosynthetic pathway and is an antimicrobial target. We used an inhibitor-in-pieces approach, based on the previously reported inhibitor DAHP oxime, to screen inhibitor fragments in the presence and absence of glycerol 3-phosphate to occupy the distal end of the active site. This led to DAHP hydrazone, the most potent inhibitor to date, = 10 ± 1 nM.

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.

The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K.

Eliminating Competition: Characterizing and Eliminating Competitive Binding at Separate Sites between DAHP Synthase's Essential Metal Ion and the Inhibitor DAHP Oxime.

3-Deoxy-d- arabinoheptulosonate 7-phosphate (DAHP) oxime is a transition state mimic inhibitor of bacterial DAHP synthase, with K = 1.5 μM and a residence time of t = 83 min. Unexpectedly, DAHP oxime inhibition is competitive with respect to the essential metal ion, Mn, even though the inhibitor and metal ion do not occupy the same physical space in the active site.

Potent Inhibition of 3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) Synthase by DAHP Oxime, a Phosphate Group Mimic.

3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate pathway. It catalyzes an aldol-like reaction of phosphoenolpyruvate (PEP) with erythrose 4-phosphate (E4P) to form DAHP. The kinetic mechanism was rapid equilibrium sequential ordered ter ter, with the essential divalent metal ion, Mn, binding first, followed by PEP and E4P.