National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01-67167
United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01-AI062520
United States
Citation
Journal: Science / Year: 2020 Title: Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Authors: Stephanie M Bester / Guochao Wei / Haiyan Zhao / Daniel Adu-Ampratwum / Naseer Iqbal / Valentine V Courouble / Ashwanth C Francis / Arun S Annamalai / Parmit K Singh / Nikoloz Shkriabai / ...Authors: Stephanie M Bester / Guochao Wei / Haiyan Zhao / Daniel Adu-Ampratwum / Naseer Iqbal / Valentine V Courouble / Ashwanth C Francis / Arun S Annamalai / Parmit K Singh / Nikoloz Shkriabai / Peter Van Blerkom / James Morrison / Eric M Poeschla / Alan N Engelman / Gregory B Melikyan / Patrick R Griffin / James R Fuchs / Francisco J Asturias / Mamuka Kvaratskhelia / Abstract: The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing ...The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.
History
Deposition
Feb 20, 2020
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Header (metadata) release
Mar 18, 2020
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Map release
Oct 21, 2020
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Update
Mar 6, 2024
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Current status
Mar 6, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: Talos Arctica / Image courtesy: FEI Company
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Image processing
Final reconstruction
Number classes used: 96392 Applied symmetry - Helical parameters - Δz: 7.61 Å Applied symmetry - Helical parameters - Δ&Phi: 150.32 ° Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric) Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 6.08 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.0) Details: A non-helical approach (RASTR) to calculate a volume from the same subset of data used for helical analysis. The position and rotation to the center of a single hexamer in the final helical ...Details: A non-helical approach (RASTR) to calculate a volume from the same subset of data used for helical analysis. The position and rotation to the center of a single hexamer in the final helical volume was determined and used along the final refined helical rise and twist to extract a total of 245050 unique particles from which surrounding tube density was subtracted by reprojection using Relion. The resulting stack of 245050 particles, each extracted into a 192 multiple 192 pixel box centered around the chosen asymmetric unit for each subtracted volume, was imported into Cryosparc. 2D clustering and ab-initio heterogeneous reconstruction with 4 volumes were then used to select a subset of 96392 particle images. These images, along with the cleanest reference from ab-initio volume determination were then used to obtain a volume through 3D Refinement. Number images used: 245050
Segment selection
Number selected: 146291 / Software - Name: RELION (ver. 3.0.4) Details: A total of 208,225helical segments were extracted from manually selected, well-ordered helical tubes using Relion
Startup model
Type of model: OTHER Details: Featureless cylindrical shell as initial model made by Relion.
Final angle assignment
Type: NOT APPLICABLE / Software - Name: RELION (ver. 3.0.4) / Software - details: 3D refinement / Details: 3D refinement in Relion
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