title: Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics.
abstract: Retroviral capsid proteins are conserved structurally but assemble into different morphologies. The mature human immunodeficiency virus-1 (HIV-1) capsid is best described by a 'fullerene cone' model, 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, a carboxy-terminal domain (CTD) comprising four α-helices, and a flexible linker with a 310-helix connecting the two structural domains. Structures of the capsid-protein assembly units have been determined by X-ray crystallography; 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, 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.
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Gongpu
authors.initials: G
authors.lastname: Zhao
authors.forename: Juan R
authors.initials: JR
authors.lastname: Perilla
authors.forename: Ernest L
authors.initials: EL
authors.lastname: Yufenyuy
authors.forename: Xin
authors.initials: X
authors.lastname: Meng
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Jiying
authors.initials: J
authors.lastname: Ning
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gronenborn
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
authors.forename: Peijun
authors.initials: P
authors.lastname: Zhang
mesh_terms: D002213:Capsid / Q000737:chemistry* / Q000648:ultrastructure*; D036022:Capsid Proteins / Q000737:chemistry / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D015497:HIV-1 / Q000737:chemistry* / Q000648:ultrastructure*; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000648:ultrastructure; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D036022:Capsid Proteins; D054298:Human Immunodeficiency Virus Proteins