Identification of the initial nucleocapsid recognition element in the HIV-1 RNA packaging signal
Pengfei Ding, Siarhei Kharytonchyk, Alexis Waller, Ugonna Mbaekwe, Sapna Basappa, Nansen Kuo, Heather M. Frank, Christina Quasney, Aaron Kidane, C.A. Swanson, Verna Van, Mitali Sarkar‐Tyson, Emily Cannistraci, Ridhi Chaudhary, Hana Flores, Alice Telesnitsky, Michael F. Summers
Abstract
). The four initial binding sites with highest affinity reside near two symmetrically equivalent three-way junction structures. Unlike the other high-affinity sites, which bind NC with exothermic energetics, binding to these sites occurs endothermically due to concomitant unwinding of a weakly base-paired [UUUU]:[GGAG] helical element. Mutations that stabilize base pairing within this element eliminate NC binding to this site and severely impair RNA packaging into virus-like particles. NMR studies reveal that a recently discovered small-molecule inhibitor of HIV-1 RNA packaging that appears to function by stabilizing the structure of the leader binds directly to the [UUUU]:[GGAG] helix. Our findings suggest a sequential NC binding mechanism for Gag-genome assembly and identify a potential RNA Achilles' heel to which HIV therapeutics may be targeted.