Volume 15 Issue 7, July 2019

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.

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 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.

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.

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 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.

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.

Rewiring of bacterial two-component systems (TCSs) was achieved by DNA-binding domain swapping of the two largest response regulator families, which enables cross-species porting and provides a tool for identifying ligands for uncharacterized TCSs.

Sulfation of chondroitin sulfate and heparan sulfate dictates their abilities to promote axon growth via regulating the binding to the phosphatase PTPRσ and the consequences on phosphorylation of the cortactin component of the autophagy machinery.

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.

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.

Synthetic gene circuits regulated by small molecules have been used to fine-tune glycosyltransferase expression in CHO cells, providing a method to produce therapeutic monoclonal antibodies with precise glycosylation states.

A chemical proteomics strategy identifies DCAF16 as a potential ubiquitin ligase recruiter for cysteine-directed electrophilic PROTACs to promote the degradation of nuclear proteins.

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.