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A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.
A covalent ligand that targets C277 of ATP6V1A was identified resulting in enhanced v-ATPase activity, inhibition of mTORC1 signaling, increased lysosomal acidification, activation of autophagy and clearance of toxic protein aggregates.
Autophagy is a ‘self-eating’ recycling process that maintains cellular homeostasis. Autogramins were identified as small-molecule autophagy inhibitors that target the cholesterol transport protein GRAMD1A, revealing a role for cholesterol in autophagosome biogenesis.
The cholesterol-transfer protein GRAMD1A is identified as the target of the autophagy inhibitors autogramin-1 and autogramin-2. GRAMD1A is found to be required for autophagosome biogenesis.
The limited availability of small-molecule ligands for E3 ubiquitin ligases stymies the development of next-generation degraders. Two recent papers report the identification of novel, covalent and PROTAC-compatible ligands that hijack the previously untargeted ligases RNF114 and DCAF16.
The natural product nimbolide covalently reacts with a functional cysteine of the E3 ubiquitin ligase RNF114, resulting in impaired substrate recognition and degradation, enabling the use of nimbolide for targeted protein degradation.
A combination of crosslinking, X-ray crystallography, NMR, and mutagenesis provide a detailed visualization of the interactions between an acyl carrier protein and β-ketoacyl-ACP-synthase I in the Escherchia coli fatty acid synthase complex.
Optimization of triacylglycerol production in the oleaginous bacterium Rhodococcus opacus followed by pathway engineering enables the enhanced production of free fatty acids, fatty acid ethyl esters and long-chain hydrocarbons from glucose.
An inhibitor of the complement pathway of the innate immune system targets the human complement component 5 protein (C5) by binding to an interfacial pocket to prevent its proteolytic cleavage by the last enzyme of the complement pathway, C5 convertase.
A chemical proteomics strategy identifies DCAF16 as a potential ubiquitin ligase recruiter for cysteine-directed electrophilic PROTACs to promote the degradation of nuclear proteins.
This Review highlights recent structure–function insights that inform diverse pharmacologic strategies for direct targeting of BAX to alternatively reactivate or inhibit apoptosis in diseases of pathologic cell survival or premature cellular demise.
The advent of PROTACs that degrade the entire protein target rather than simply inhibiting it bring druggable yet apparently non-functional binding sites into play for medicinal chemists to do their work.
A structure-based design allows the development of a potent PROTAC to degrade BAF ATPase subunits SMARCA2 and SMARCA4 via recruitment of E3 ubiquitin ligase VHL and induce cancer cell death.
Mitochondrial energy metabolism regulates proteotoxic stress tolerance, exposing a newly discovered sensitivity to the small molecule elesclomol, which induces FDX1-mediated, copper-dependent cell death.