Journal Article

Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics

Meng, Xin, Yufenyuy, Ernest L., Schulten, Klaus, Perilla, Juan R., Ning, Jiying, Zhang, Peijun, Zhao, Gongpu, Chen, Bo, Aiken, Christopher, Ahn, Jinwoo, Gronenborn, Angela M.

2013

Overview

The structure of the HIV-1 capsid is analysed by cryo-electron microscopy and cryo-electron tomography, allowing presentation of an all-atom molecular dynamics model of the entire capsid. Atomic structure of the HIV-1 capsid Human immunodeficiency virus-1 (HIV-1), the predominant AIDS virus, contains a spheroidal capsid enclosing the viral RNA genome. As the retrovirus matures, the capsid forms through spontaneous oligomerization of the capsid protein CA. Using cryo-electron microscopy and cryo-electron tomography, combined with all-atom large-scale molecular dynamics simulations, Gongpu Zhao et al . have determined a complete atomic structure of the HIV-1 capsid. The resulting structural models reveal elements that are essential for capsid formation, stability and viral infectivity. Of special interest are the hydrophobic interactions evident in a novel three-fold interface between the carboxy-terminal domains of CA protein, a feature that appears to be unique to the mature capsid and which has previously been suggested as a potentially attractive therapeutic target. Retroviral capsid proteins are conserved structurally but assemble into different morphologies 1 . The mature human immunodeficiency virus-1 (HIV-1) capsid is best described by a ‘fullerene cone’ model 2 , 3 , in which hexamers of the capsid protein are linked to form a hexagonal surface lattice that is closed by incorporating 12 capsid-protein pentamers. HIV-1 capsid protein contains an amino-terminal domain (NTD) comprising seven α-helices and a β-hairpin 4 , 5 , a carboxy-terminal domain (CTD) comprising four α-helices 6 , 7 , and a flexible linker with a 3 10 -helix connecting the two structural domains 8 . Structures of the capsid-protein assembly units have been determined by X-ray crystallography 9 , 10 ; however, structural information regarding the assembled capsid and the contacts between the assembly units is incomplete. Here we report the cryo-electron microscopy structure of a tubular HIV-1 capsid-protein assembly at 8 Å resolution and the three-dimensional structure of a native HIV-1 core by cryo-electron tomography. The structure of the tubular assembly shows, at the three-fold interface 11 , a three-helix bundle with critical hydrophobic interactions. Mutagenesis studies confirm that hydrophobic residues in the centre of the three-helix bundle are crucial for capsid assembly and stability, and for viral infectivity. The cryo-electron-microscopy structures enable modelling by large-scale molecular dynamics simulation, resulting in all-atom models for the hexamer-of-hexamer and pentamer-of-hexamer elements as well as for the entire capsid. Incorporation of pentamers results in closer trimer contacts and induces acute surface curvature. The complete atomic HIV-1 capsid model provides a platform for further studies of capsid function and for targeted pharmacological intervention.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/114/2397 / 631/326/421 / 631/535/1258/1259 / Analysis / Capsid - chemistry / Capsid - ultrastructure / Capsid Proteins - chemistry / Capsid Proteins - ultrastructure / Chemical properties / Cryoelectron Microscopy / Crystal structure / Crystallography / Electron microscopy / HIV (Viruses) / HIV-1 - chemistry / HIV-1 - ultrastructure / Human Immunodeficiency Virus Proteins - chemistry / Human Immunodeficiency Virus Proteins - ultrastructure / Humanities and Social Sciences / Hydrophobic and Hydrophilic Interactions / letter / Methods / Microscopy / Molecular dynamics / Molecular Dynamics Simulation / multidisciplinary / Properties / Protein Multimerization / Protein Structure, Secondary / Protein Structure, Tertiary / Proteins / Science