Spotlights Cite This: J. Am. Chem. Soc. 2017, 139, 16023-16023
pubs.acs.org/JACS
Spotlights on Recent JACS Publications
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COMPUTER-GUIDED SEARCH FOR PROTEIN INHIBITION SCORES A LEADING LIGAND One strategy for modulating the effects of proteins involved in disease is to design peptides that block their harmful interaction with other proteins. Paramjit Arora, Yingkai Zhang, and colleagues have designed a peptide with strong binding affinity for the protein KIX, whose interactions with oncogenic transcription factors have been linked with leukemia (DOI: 10.1021/jacs.7b05960). KIX uses a helix-strand motif to interact with its natural binding partner, MLL, but the researchers’ first attempt of simply using a truncated helix did not replicate the binding. The team seeks to incorporate non-natural residues to compensate for the missing contacts. To obtain a more effective peptide, the researchers computationally map the binding interface between KIX and MLL to identify residues involved in the protein−protein interaction. Judicious substitution of residues in the truncated helix leads to a peptide with affinity close to that of the wild type MLL. Inhibiting the KIX-MLL interaction has been proposed in the treatment of leukemia, so this study could influence the development of therapies in this area, and advance peptidomimetic design in general. Deirdre Lockwood, Ph.D.
MODELING A PROPOSED INTERMEDIATE IN BIOCATALYTIC N2-TO-NH3 CONVERSION Nitrogen fixation, or the conversion of dinitrogen to valueadded products such as NH3, is essential for life in various microorganisms, and elucidation of the steps in this biological transformation is desirable both fundamentally and toward the design of improved synthetic catalysts. A so-called “distal” pathway has been proposed in iron-mediated catalytic N2 reduction, which involves sequential H-atom addition to the same terminal nitrogen to release NH3 and an iron nitride. However, experimental support for this hypothesis has remained elusive. Jonas Peters and colleagues have now succeeded in identifying terminal iron nitride formation in the course of mechanistic studies of a model N2-to-NH3 catalyst (DOI: 10.1021/jacs.7b09364). The authors show that a nitrogen-fixing iron complex binds nitrogen end-on and can be protonated to form a neutral Fe(NNH2) intermediate, which then undergoes N−N bond cleavage to form the terminal iron nitride [FeIV-N]+ and NH3. The study highlights the importance of high ligand covalency in affording redox stabilization to the iron center over the course of the multielectron transformation. This system provides a simple model for the analogous redox modulation effected by more complex nitrogenase enzymes. Katie Meihaus, Ph.D.
TAKING A DIFFERENT VIEW OF A LIGHT-CATCHING PROTEIN Capturing light from the sun to drive biological reactions is fundamental for life, but the molecular details of how that works remain mysterious. At the core of light-capturing proteorhodopsins is a retinal molecule, which undergoes a conformational shift upon excitation that is little understood. To observe the conformational changes that occur in retinal and the surrounding protein residues upon light absorption, Clemens Glaubitz and colleagues use dynamic nuclear polarization solid-state NMR spectroscopy to visualize a proteorhodopsin (DOI: 10.1021/jacs.7b05061). They employ a novel approach to cryo-trap the retinal in the light-induced K and M states. The researchers label retinal with 13C and incorporate that into 15N-labeled proteorhodopsin. They then evaluate the molecule in its ground state, K state, and M state. The spectra show significant chemical shift changes between states for the retinal polyene chain, suggesting the chromophore becomes distorted during the ground-to-K-state transition. Furthermore, the researchers identify two different M -states, related to a deprotonation-driven reorientation of the retinal’s Schiff base. Using this approach, scientists may be able to provide insight into how similar molecular designssuch as that observed in proteorhodopsin and bacteriorhodopsincan manifest in a wide range of biological functions. Erika Gebel Berg, Ph.D.
COPPER MEDIATES FIRST SITE-SELECTIVE ARYLATION OF CARBOHYDRATES Mark Taylor and colleagues report a site-selective, coppermediated O-arylation of sugar derivatives to render aryl ethers (DOI: 10.1021/jacs.7b09420). Sugar-derived aryl ethers could be used in medicinal chemistry, as tags in glycobiology research, or as protecting groups for synthetic carbohydrate chemistry, but their preparation is challenging. Reactions using transition metals to connect aryl groups with amines, alcohols, and thiols on peptides have provided new ways to synthesize pharmaceuticals, natural products, and polymers. However, there are few equivalent reactions to arylate hydroxy groups like those found on sugars. Taylor and his team use aryl boronic acids to site-selectively arylate various pyranosides and furanosides. In the presence of copper, the reagents combine to form a sugar-derived boronic ester. This group serves as a temporary protecting group while also causing an apparent acceleration of the site-selective arylation. The reaction yields are comparable to those of known methods of preparing phenyl ethers from protected carbohydrates. This reactivity enables the selective functionalization of carbohydrate derivatives that would otherwise be difficult to realize by existing means. Melissae Fellet, Ph.D.
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© 2017 American Chemical Society
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Published: November 15, 2017 16023
DOI: 10.1021/jacs.7b11792 J. Am. Chem. Soc. 2017, 139, 16023−16023
