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Cited by 801HIV Research and TreatmentAdvanced Electron Microscopy Techniques and ApplicationsProtein Structure and Dynamics

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

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Zhao, Gongpu, Perilla, Juan R., Yufenyuy, Ernest L., Meng, Xin, Chen, Bo, Ning, Jiying, Ahn, Jinwoo, Gronenborn, Angela M. +3 more·2013·Nature
DOI 10.1038/nature12162PMC PMC3729984
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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.

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  • While in-virus structures are currently lacking, in vitro studies indicate that the arrangement of CA in mature retroviruses is well conserved.

    “While in-virus structures are currently lacking, these in vitro studies indicate that the arrangement of CA in mature retroviruses is well conserved”

    From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [43]

    The main text (page not provided) says retroviral CA proteins share a common N-terminal fold and all form hexamers, supporting a conserved assembly building block. It does not establish that the overall arrangement of CA is well conserved across mature retroviruses; it also reports different capsid morphologies and a tomographic structure of a native HIV-1 core, so the claim that in-virus structures are lacking needs qualification. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The variable local curvatures of the hexameric CA lattice require considerable structural flexibility of the CA lattice, which has been suggested to be accommodated by the flexible linker between CA-NTD and CA-CTD, by rotations around the dimeric CA-CTD interface, and by structural changes at the trimeric CA-CTD interface.

    “This requires considerable structural flexibility of the CA lattice that has been suggested to be accommodated by the flexible linker between CA-NTD and CA-CTD [44,45 ], by rotations around the dimeric CA-CTD interface [43 ], and by structural changes at the trimeric CA-CTD interface”

    From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [43]

  • The CA-CTDs are located beneath the hexameric ring and form dimeric inter-hexamer interactions involving mainly hydrophobic interactions between residues on helix 9 at the local twofold and residues on helix 10 at the local three-fold.

    “The CA-CTDs are located beneath the hexameric ring and form dimeric inter-hexamer interactions involving mainly hydrophobic interactions between residues on helix 9 at the local twofold [6,53] and residues on helix 10 at the local three-fold”

    From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [43]

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Research works printed but not linked: 26

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Authors
Zhao, G., Perilla, J. R., Yufenyuy, E. L., Meng, X., Chen, B., Ning, J., Ahn, J., Gronenborn, A. M., Schulten, K., Aiken, C., & Zhang, P.
Affiliations
  • University of Pittsburgh (US)
  • University of Illinois Urbana-Champaign (US)
  • University of Central Florida (US)
Corresponding author
  • Schulten, Klaus
  • Aiken, Christopher
  • Zhang, Peijun
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-05
Volume
497
Issue
7451
Pages
643-646
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12162
PMC
PMC3729984
OpenAlex
W2021064626
Cited by
801
References
2
Citations by year
2026: 29 · 2025: 35 · 2024: 44 · 2023: 50 · 2022: 58 · 2021: 63 · 2020: 58 · 2019: 52 · 2018: 73 · 2017: 66 · 2016: 83 · 2015: 83 · 2014: 84 · 2013: 23
FWCI
41.79
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Journal of International Crisis and Risk Communication Research (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (P50GM082251, P41GM104601, R01GM085043)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
HIV-1 capsid, capsid assembly, hydrophobic interactions, three-helix bundle, C-terminal domain, viral infectivity, capsid stability, viral core structure, cryo-electron tomography, cryo-electron microscopy, all-atom molecular dynamics, HIV-1 reverse transcriptase, antiviral drug targets
MeSH terms
Capsid, HIV-1, Protein Structure, Secondary, Protein Structure, Tertiary, Cryoelectron Microscopy, Capsid Proteins, Human Immunodeficiency Virus Proteins, Protein Multimerization, Molecular Dynamics Simulation, Hydrophobic and Hydrophilic Interactions

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