Molecular mechanism of distinct chemokine engagement and functional divergence of the human Duffy antigen receptor.

The Duffy antigen receptor is a seven-transmembrane (7TM) protein expressed primarily at the surface of red blood cells and displays strikingly promiscuous binding to multiple inflammatory and homeostatic chemokines. It serves as the basis of the Duffy blood group system in humans and also acts as the primary attachment site for malarial parasite Plasmodium vivax and pore-forming toxins secreted by Staphylococcus aureus. Here, we comprehensively profile transducer coupling of this receptor, discover potential non-canonical signaling pathways, and determine the cryoelectron microscopy (cryo-EM) structure in complex with the chemokine CCL7. The structure reveals a distinct binding mode of chemokines, as reflected by relatively superficial binding and a partially formed orthosteric binding pocket. We also observe a dramatic shortening of TM5 and 6 on the intracellular side, which precludes the formation of the docking site for canonical signal transducers, thereby providing a possible explanation for the distinct pharmacological and functional phenotype of this receptor.

Mechanochemical Cascade Cyclization of Cyclopropyl Ketones with 1,2-Diamino Arenes for the Direct Synthesis of 1,2-Disubstituted Benzimidazoles†.

A mechanochemical synthesis of 1,2-disubstituted benzimidazoles from donor-acceptor cyclopropyl ketones and 1,2-diaminoarenes under metal-free and solventless conditions is reported. The reaction does not require inert conditions and is promoted by a stoichiometric amount of 1,1,1,3,3,3-hexafluoroisopropanol. This cascade reaction involves ring-opening, cyclization, and retro-Mannich reaction of cyclopropyl ketones with aryl 1,2-diamines. Compared to its solution-phase counterpart, this mechanochemical approach shows fast reactivity (24 vs 1.5 h). Mechanistic investigations by electrospray ionization mass spectrometry helped us to propose the reaction mechanism.