NifB uses an RS–K1–K2 triad to assemble the L-cluster, a [Fe8S9C] precursor of the nitrogenase cofactor. The RS module cleaves SAM to form the 5′-dA radical, K1 serves structural/SAM-sensing roles, a...

Association of the L-cluster with the nitrogenase assembly proteins NifEN (NifENL) or NifB (NifBL) intrinsically endows these proteins with N2-reducing activity, enabling in vitro N2-reduction by Nif....

Dr. Benjamin Morehouse uncovers ancient immune protein SIRa1, a breakthrough that could combat antimicrobial resistance by targeting host immunity instead of pathogens.

Structural insights into the assembly of the complex nitrogenase cofactor are scarce. Now, cryo-EM and AlphaFold analyses of NifEN, which converts the precursor (L-cluster) to a mature cofactor (M-clu...

The enzymatic synthesis of azetidines is a prime example of the superiority natural systems often show over laboratory syntheses, but how nature achieves such difficult transformations in mild conditi...

Methylthio-alkane reductases are recently discovered enzymes that can produce methanethiol and small hydrocarbons from methylated sulfur compounds. Now the cryo-EM structure of a methylthio-alkane red...

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Heterologous synthesis of a nitrogenase analog (NifH/NifEN) in E. coli enables N2 reduction and incorporation of N into biomass.

Nature Communications - CryoEM snapshots of the nitrogenase-like DPOR protein complex captured during turnover reveal that asymmetric conformational changes, substrate recognition, and an interplay...

Nitrogenase catalyzes the reduction of N2 to NH3 at its active site cofactor. Catalysis by the homologous V- and Mo-nitrogenases involves the same dynamic belt-S mobilization that occurs asymmetricall...

Iron–sulfur clusters are essential protein cofactors synthesized in human mitochondria by an NFS1-ISD11-ACP-ISCU2-FXN assembly complex. Surprisingly, researchers have discovered three distinct quaternary structures for cysteine desulfurase subcomplexes, which display similar interactions between NFS1-ISD11-ACP protomeric units but dramatically different dimeric interfaces between the protomers. Although the role of these different architectures is unclear, possible functions include regulating activity and promoting the biosynthesis of distinct sulfur-containing biomolecules. Here, crystallography, native ion-mobility mass spectrometry, and chromatography methods reveal the Fe–S assembly subcomplex exists as an equilibrium mixture of these different quaternary structures. Isotope labeling and native mass spectrometry experiments show that the NFS1-ISD11-ACP complexes disassemble into protomers, which can then undergo exchange reactions and dimerize to reform native complexes. Single crystals isolated in distinct architectures have the same activity profile and activation by the Friedreich’s ataxia (FRDA) protein frataxin (FXN) when rinsed and dissolved in assay buffer. These results suggest FXN functions as a “molecular lock” and shifts the equilibrium toward one of the architectures to stimulate the cysteine desulfurase activity and promote iron–sulfur cluster biosynthesis. An NFS1-designed variant similarly shifts the equilibrium and partially replaces FXN in activating the complex. We propose that eukaryotic cysteine desulfurases are unusual members of the morpheein class of enzymes that control their activity through their oligomeric state. Overall, the findings support architectural switching as a regulatory mechanism linked to FXN activation of the human Fe–S cluster biosynthetic complex and provide new opportunities for therapeutic interventions of the fatal neurodegenerative disease FRDA.

Animal toxins can modulate action potentials and are important leads for therapeutics. Here, the authors use cryo-EM to show the interaction of the tarantula venom peptide Protoxin-I with a human volt...