Structural basis of HIV-1 capsid recognition by PF74 and CPSF6

被引:202
作者
Bhattacharya, Akash [1 ,2 ]
Alam, Steven L. [3 ]
Fricke, Thomas [4 ]
Zadrozny, Kaneil [5 ]
Sedzicki, Jaroslaw [5 ]
Taylor, Alexander B. [1 ,2 ]
Demeler, Borries [1 ,2 ]
Pornillos, Owen [5 ,6 ]
Ganser-Pornillos, Barbie K. [5 ]
Diaz-Griffero, Felipe [4 ]
Ivanov, Dmitri N. [1 ,2 ]
Yeager, Mark [5 ,6 ,7 ,8 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA
[2] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA
[3] Univ Utah, Dept Biochem, Salt Lake City, UT 84112 USA
[4] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA
[5] Univ Virginia, Sch Med, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA
[6] Univ Virginia, Sch Med, Ctr Membrane Biol, Charlottesville, VA 22908 USA
[7] Univ Virginia, Sch Med, Cardiovasc Res Ctr, Charlottesville, VA 22908 USA
[8] Univ Virginia, Sch Med, Div Cardiovasc Med, Dept Med, Charlottesville, VA 22908 USA
关键词
HIV-1 CA protein; drug discovery; X-ray crystallography; fluorescence polarization; isothermal calorimetry; HUMAN-IMMUNODEFICIENCY-VIRUS; CRYOELECTRON MICROSCOPY; NUCLEAR IMPORT; INFECTION; DOMAIN; REPLICATION; INHIBITION; TNPO3; CORE; GAG;
D O I
10.1073/pnas.1419945112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Upon infection of susceptible cells by HIV-1, the conical capsid formed by similar to 250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. The capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host-virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the Cterminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD-CTD interface is critical for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD-CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD-CTD interface is a specificmolecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus.
引用
收藏
页码:18625 / 18630
页数:6
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