7MKC

N74D mutant of the HIV-1 capsid protein in complex with PF-3450074 (PF74)

Summary for 7MKC

• Entry DOI: 10.2210/pdb7mkc/pdb
• Related: 7MN0
• Descriptor: capsid protein, N-METHYL-NALPHA-[(2-METHYL-1H-INDOL-3-YL)ACETYL]-N-PHENYL-L-PHENYLALANINAMIDE, IODIDE ION, ... (4 entities in total)
• Functional Keywords: hiv-1 capsid protein, hexmer, ca-targeting antiviral, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 26818.36

Authors

Kirby, K.A.,Sarafianos, S.G. (deposition date: 2021-04-23, release date: 2022-05-04, Last modification date: 2024-11-20)

Primary citation

Selyutina, A.,Simons, L.M.,Kirby, K.A.,Bulnes-Ramos, A.,Hu, P.,Sarafianos, S.G.,Hultquist, J.F.,Diaz-Griffero, F.
TRIM5alpha Restriction of HIV-1-N74D Viruses in Lymphocytes Is Caused by a Loss of Cyclophilin A Protection.
Viruses, 14:363-, 2022

PubMed Abstract: The core of HIV-1 viruses bearing the capsid change N74D (HIV-1-N74D) do not bind the human protein CPSF6. In primary human CD4 T cells, HIV-1-N74D viruses exhibit an infectivity defect when compared to wild-type. We first investigated whether loss of CPSF6 binding accounts for the loss of infectivity. Depletion of CPSF6 in human CD4 T cells did not affect the early stages of wild-type HIV-1 replication, suggesting that defective infectivity in the case of HIV-1-N74D viruses is not due to the loss of CPSF6 binding. Based on our previous result that cyclophilin A (Cyp A) protected HIV-1 from human tripartite motif-containing protein 5α (TRIM5α) restriction in CD4 T cells, we found that depletion of TRIM5α in CD4 T cells rescued the infectivity of HIV-1-N74D, suggesting that HIV-1-N74D cores interacted with TRIM5α. Accordingly, TRIM5α binding to HIV-1-N74D cores was increased compared with that of wild-type cores, and consistently, HIV-1-N74D cores lost their ability to bind Cyp A. In agreement with the notion that N74D capsids are defective in their ability to bind Cyp A, we found that HIV-1-N74D viruses were 20-fold less sensitive to TRIMCyp restriction when compared to wild-type viruses in OMK cells. Structural analysis revealed that N74D hexameric capsid protein in complex with PF74 is different from wild-type hexameric capsid protein in complex with PF74, which explains the defect of N74D capsids to interact with Cyp A. In conclusion, we showed that the decreased infectivity of HIV-1-N74D in CD4 T cells is due to a loss of Cyp A protection from TRIM5α restriction activity.

PubMed: 35215956
DOI: 10.3390/v14020363

Experimental method

X-RAY DIFFRACTION (2.65 Å)