Atomic-resolution structure of HIV-1 capsid tubes by magic-angle spinning NMR.

Abstract

HIV-1 capsid plays multiple key roles in viral replication, and inhibition of capsid assembly is an attractive target for therapeutic intervention. Here, we report the atomic-resolution structure of the capsid protein (CA) tubes, determined by magic-angle-spinning NMR and data-guided molecular dynamics simulations. Functionally important regions, including the NTD β-hairpin, the cyclophilin A loop, residues in the hexamer center pore, and the NTD-CTD linker region, are well defined. The structure of individual CA chains, their arrangement in the pseudo-hexameric units of the tube and the inter-hexamer interfaces are consistent with those in intact capsid cores and substantially different from the organization in crystal structures, which featured flat hexamers. The inherent curvature in the CA tubes is controlled by conformational variability of residues in the linker region and of dimer and trimer interfaces. The present structure reveals atomic-level detail into capsid architecture and provides important guidance for the design of novel capsid inhibitors.