6B2H

P38A/T216I mutant of the HIV-1 capsid protein

Summary for 6B2H

• Entry DOI: 10.2210/pdb6b2h/pdb
• Related: 4XFX 6B2G 6B2I 6B2J 6B2K
• Descriptor: HIV-1 capsid protein, IODIDE ION, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: hiv-1 capsid protein, hexamer, p38a/t216i mutant, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 26590.58

Authors

Gres, A.T.,Kirby, K.A.,Sarafianos, S.G. (deposition date: 2017-09-20, release date: 2018-09-26, Last modification date: 2023-10-04)

Primary citation

Gres, A.T.,Kirby, K.A.,McFadden, W.M.,Du, H.,Liu, D.,Xu, C.,Bryer, A.J.,Perilla, J.R.,Shi, J.,Aiken, C.,Fu, X.,Zhang, P.,Francis, A.C.,Melikyan, G.B.,Sarafianos, S.G.
Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization.
Nat Commun, 14:5614-5614, 2023

PubMed Abstract: 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-CA inter-hexamer interactions, variable R18-ring pore sizes, and flipped N-terminal β-hairpin. (3) Altered conformations of E45A α9-helices compared to WT, E45A/R132T, WT, WT, and WT 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.

PubMed: 37699872
DOI: 10.1038/s41467-023-41197-7

Experimental method

X-RAY DIFFRACTION (2.6 Å)