Problems making proteins kills nerve cells: Neurodegeneration is associated with a variety of different diseases, but its cellular roots are often obscure. Ishimura et al. find that mutant mice whose brain cells start to die rapidly soon after birth have lost the function of two vital cellular components (see the Perspective by Darnell). The first is a protein that releases stalled ribosomes stuck on messenger RNA (mRNA); the second is a transfer RNA (tRNA), which reads the code for arginine in the mRNA. This tRNA is expressed predominantly in the central nervous system. The lack of the tRNA leads to increased ribosomal stalling at arginine codons, which, when left uncorrected, blocks protein synthesis and proves fatal. Science , this issue p. 455 ; see also p. 378

The crystal structure of prolyl tRNA synthetase simultaneously bound to its substrate ATP and its inhibitor halofuginone, a derivative of a compound used to treat malaria, indicates that (through interactions with ATP) halofuginone occupies both the amino acid and tRNA binding sites on the synthetase, revealing a new model for developing synthetase inhibitors. The halogenated derivative of an active ingredient in Chinese traditional medicine used as an antimalarial treatment, halofuginone (HF), is currently in clinical trials. HF is known to inhibit prolyl-tRNA synthetase (ProRS), resulting in an accumulation of uncharged tRNAs. Paul Schimmel and colleagues have solved the crystal structure of ProRS bound to ATP and HF. They find that ATP helps to lock the drug on ProRS so that it occupies two substrate binding sites — one for proline and the other for the 3′ end of the tRNA. The authors suggest that this information might be used to develop other synthetase inhibitors that would occupy both sites in a modular fashion. Febrifugine is the active component of the Chinese herb Chang Shan (Dichroa febrifuga Lour.)1,2, which has been used for treating malaria-induced fever for about 2,000 years. Halofuginone (HF), the halogenated derivative of febrifugine, has been tested in clinical trials for potential therapeutic applications in cancer and fibrotic disease3,4,5,6. Recently, HF was reported to inhibit TH17 cell differentiation by activating the amino acid response pathway7, through inhibiting human prolyl-transfer RNA synthetase (ProRS) to cause intracellular accumulation of uncharged tRNA8,9. Curiously, inhibition requires the presence of unhydrolysed ATP. Here we report an unusual 2.0 Å structure showing that ATP directly locks onto and orients two parts of HF onto human ProRS, so that one part of HF mimics bound proline and the other mimics the 3′ end of bound tRNA. Thus, HF is a new type of ATP-dependent inhibitor that simultaneously occupies two different substrate binding sites on ProRS. Moreover, our structure indicates a possible similar mechanism of action for febrifugine in malaria treatment. Finally, the elucidation here of a two-site modular targeting activity of HF raises the possibility that substrate-directed capture of similar inhibitors might be a general mechanism that could be applied to other synthetases.

Charcot–Marie–Tooth diseases are hereditary peripheral neuropathies for which there are currently no effective therapies; here the type 2D subtype of these diseases is shown to be caused by mutations impeding a signalling pathway necessary for motor neuron survival. Charcot–Marie–Tooth diseases are hereditary peripheral neuropathies for which there are currently no effective therapies. The type 2D subtype of these diseases (CMT2D) is associated with dominant mutations in the enzyme glycyl-tRNA synthetase (GlyRS). Here the molecular mechanism by which these mutations cause neuropathy is shown to involve suppression of a signalling pathway necessary for motor neuron survival. CMT2D mutations alter the conformation of GlyRS, enabling it to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1, and indicates that the VEGF–Nrp1 signalling axis is an actionable target for treating CMT2D. Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes1. Charcot–Marie–Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies2,3. A subtype of these diseases—CMT type 2D (CMT2D)—is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function4. How mutations in GlyRS (GlyRSCMT2D) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRSCMT2D acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRSCMT2D to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRSCMT2D that antagonizes the VEGF–Nrp1 interaction, and indicate that the VEGF–Nrp1 signalling axis is an actionable target for treating CMT2D.