6b2k

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E45A/R132T mutant of HIV-1 capsid protein

Structural highlights

6b2k is a 1 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GAG_HV1N5 Matrix protein p17 targets Gag and Gag-Pol polyproteins to the plasma membrane via a multipartite membrane binding signal, that includes its myristoylated N-terminus. Also mediates nuclear localization of the preintegration complex. Implicated in the release from host cell mediated by Vpu. Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex. Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. p6-gag plays a role in budding of the assembled particle by interacting with the host class E VPS proteins TSG101 and PDCD6IP/AIP1 (By similarity).

Publication Abstract from PubMed

HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site mutations R132T and T216I rescue infectivity. Capsid lattice stability was studied by solving seven crystal structures (in native background), including P38A, P38A/T216I, E45A, E45A/R132T CA, using molecular dynamics simulations of lattices, cryo-electron microscopy of assemblies, time-resolved imaging of uncoating, biophysical and biochemical characterization of assembly and stability. We report pronounced and subtle, short- and long-range rearrangements: (1) A38 destabilized hexamers by loosening interactions between flanking CA protomers in P38A but not P38A/T216I structures. (2) Two E45A structures showed unexpected stabilizing CA(NTD)-CA(NTD) inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal beta-hairpin. (3) Altered conformations of E45A(a) alpha9-helices compared to WT, E45A/R132T, WT(PF74), WT(Nup153), and WT(CPSF6) decreased PF74, CPSF6, and Nup153 binding, and was reversed in E45A/R132T. (4) An environmentally sensitive electrostatic repulsion between E45 and D51 affected lattice stability, flexibility, ion and water permeabilities, electrostatics, and recognition of host factors.

Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization.,Gres AT, Kirby KA, McFadden WM, Du H, Liu D, Xu C, Bryer AJ, Perilla JR, Shi J, Aiken C, Fu X, Zhang P, Francis AC, Melikyan GB, Sarafianos SG Nat Commun. 2023 Sep 12;14(1):5614. doi: 10.1038/s41467-023-41197-7. PMID:37699872^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gres AT, Kirby KA, McFadden WM, Du H, Liu D, Xu C, Bryer AJ, Perilla JR, Shi J, Aiken C, Fu X, Zhang P, Francis AC, Melikyan GB, Sarafianos SG. Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization. Nat Commun. 2023 Sep 12;14(1):5614. PMID:37699872 doi:10.1038/s41467-023-41197-7