Atomic-level modelling of the HIV capsid

Abstract

The human immunodeficiency virus 1 (HIV-1) virion has a cone-shaped core composed of capsid proteins, which take either pentameric or hexameric form. Mark Yeager and colleagues had previously solved the crystal structure of the capsid hexamer. Now they provide the structure of the pentamer, which allows them to propose the first atomic-level model of the mature HIV capsid. The HIV virion has a cone-shaped core composed of capsid proteins, which take either pentameric or hexameric form. The crystal structure of the capsid hexamer had been solved previously. Now the structure of the pentamer is provided, which allows the proposal of the first atomic-level model of the mature HIV capsid. The mature capsids of human immunodeficiency virus type 1 (HIV-1) and other retroviruses are fullerene shells, composed of the viral CA protein, that enclose the viral genome and facilitate its delivery into new host cells1. Retroviral CA proteins contain independently folded amino (N)- and carboxy (C)-terminal domains (NTD and CTD) that are connected by a flexible linker2,3,4. The NTD forms either hexameric or pentameric rings, whereas the CTD forms symmetric homodimers that connect the rings into a hexagonal lattice3,5,6,7,8,9,10,11,12,13. We previously used a disulphide crosslinking strategy to enable isolation and crystallization of soluble HIV-1 CA hexamers11,14. Here we use the same approach to solve the X-ray structure of the HIV-1 CA pentamer at 2.5 Å resolution. Two mutant CA proteins with engineered disulphides at different positions (P17C/T19C and N21C/A22C) converged onto the same quaternary structure, indicating that the disulphide-crosslinked proteins recapitulate the structure of the native pentamer. Assembly of the quasi-equivalent hexamers and pentamers requires remarkably subtle rearrangements in subunit interactions, and appears to be controlled by an electrostatic switch that favours hexamers over pentamers. This study completes the gallery of substructures describing the components of the HIV-1 capsid and enables atomic-level modelling of the complete capsid. Rigid-body rotations around two assembly interfaces appear sufficient to generate the full range of continuously varying lattice curvature in the fullerene cone.