6AXW

Structure of the I124A mutant of the HIV-1 capsid protein

6AXW の概要

• エントリーDOI: 10.2210/pdb6axw/pdb
• 関連するPDBエントリー: 4XFX 6AXR
• 分子名称: HIV-1 capsid protein, IODIDE ION, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: hiv-1 capsid protein, hexamer, i124a mutant, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26971.85

構造登録者

Gres, A.T.,Kirby, K.A.,Sarafianos, S.G. (登録日: 2017-09-07, 公開日: 2018-09-12, 最終更新日: 2024-10-30)

主引用文献

Novikova, M.,Adams, L.J.,Fontana, J.,Gres, A.T.,Balasubramaniam, M.,Winkler, D.C.,Kudchodkar, S.B.,Soheilian, F.,Sarafianos, S.G.,Steven, A.C.,Freed, E.O.
Identification of a Structural Element in HIV-1 Gag Required for Virus Particle Assembly and Maturation.
MBio, 9:-, 2018

PubMed Abstract: Late in the HIV-1 replication cycle, the viral structural protein Gag is targeted to virus assembly sites at the plasma membrane of infected cells. The capsid (CA) domain of Gag plays a critical role in the formation of the hexameric Gag lattice in the immature virion, and, during particle release, CA is cleaved from the Gag precursor by the viral protease and forms the conical core of the mature virion. A highly conserved Pro-Pro-Ile-Pro (PPIP) motif (CA residues 122 to 125) [PPIP(122-125)] in a loop connecting CA helices 6 and 7 resides at a 3-fold axis formed by neighboring hexamers in the immature Gag lattice. In this study, we characterized the role of this PPIP(122-125) loop in HIV-1 assembly and maturation. While mutations P123A and P125A were relatively well tolerated, mutation of P122 and I124 significantly impaired virus release, caused Gag processing defects, and abolished infectivity. X-ray crystallography indicated that the P122A and I124A mutations induce subtle changes in the structure of the mature CA lattice which were permissive for assembly of CA tubes. Transmission electron microscopy and cryo-electron tomography demonstrated that the P122A and I124A mutations induce severe structural defects in the immature Gag lattice and abrogate conical core formation. Propagation of the P122A and I124A mutants in T-cell lines led to the selection of compensatory mutations within CA. Our findings demonstrate that the CA PPIP(122-125) loop comprises a structural element critical for the formation of the immature Gag lattice. Capsid (CA) plays multiple roles in the HIV-1 replication cycle. CA-CA domain interactions are responsible for multimerization of the Gag polyprotein at virus assembly sites, and in the mature virion, CA monomers assemble into a conical core that encapsidates the viral RNA genome. Multiple CA regions that contribute to the assembly and release of HIV-1 particles have been mapped and investigated. Here, we identified and characterized a Pro-rich loop in CA that is important for the formation of the immature Gag lattice. Changes in this region disrupt viral production and abrogate the formation of infectious, mature virions. Propagation of the mutants in culture led to the selection of second-site compensatory mutations within CA. These results expand our knowledge of the assembly and maturation steps in the viral replication cycle and may be relevant for development of antiviral drugs targeting CA.

PubMed: 30327442
DOI: 10.1128/mBio.01567-18

実験手法

X-RAY DIFFRACTION (2.4 Å)