Inositol Hexakisphosphate Promotes Open Pore State in HIV Capsid Protein Lattice by Reconfiguring Subunit Contacts.
4 affiliations
- 1Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, 9747 AGGroningen, The Netherlands.
- 2Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Campus of the Universidad Autónoma de Madrid, 28049Madrid, Spain.
- 3Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware19716, United States.
- 4Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049Madrid, Spain.
Abstract
The mature human immunodeficiency virus (HIV-1) capsid is composed of approximately 250 capsid protein hexamers, each containing a central pore delimited by a β-hairpin and an α-helix from each monomer. The cellular metabolite inositol hexakisphosphate (IP6) binds this pore and modulates translocation of nucleoside triphosphates into the capsid, where they fuel reverse transcription of the viral genome. However, the mechanism by which IP6 modulates the pore conformation is poorly understood. Averaged structural models of the HIV-1 capsid protein lattice have shed some light on this mechanism but lack information on the dynamic behavior of individual hexamers that could provide deeper mechanistic insights. Here we visualized in real time by high-speed atomic force microscopy the asynchronous motions of individual hexamer pores in the presence or absence of IP6, identifying dynamic transitions between two major states. Quantitative analysis enabled estimation of the IP6-induced pore conformations and populations. Constant-pH molecular dynamics simulations further reveal that IP6 induces contact rewiring at the pore entrance, stabilizing the open state through coordinated rearrangement of intersubunit interactions. Consistently, mechanical fatigue assays show that IP6 markedly enhances the resistance of the capsid lattice to mechanical fatigue, revealing its role as a mechanically stabilized nanomaterial. Together, these results establish IP6 as a proviral regulator that couples nanoscale pore dynamics, intersubunit contact reconfiguration, and mechanical resilience of the HIV-1 capsid, providing a unified mechanistic framework for its role in viral replication.
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BibTeX
@article{knelissen2026inositol,
title = {{Inositol Hexakisphosphate Promotes Open Pore State in HIV Capsid Protein Lattice by Reconfiguring Subunit Contacts.}},
author = {Yari Katar Knelissen and Judith Escrig and Amanda C Macke and Sruthi Sudhakar and Santos Domínguez-Zotes and Sourav Maity and Mauricio G Mateu and Juan R Perilla and Wouter H Roos and Alejandro Valbuena},
journal = {ACS nano},
year = {2026},
month = oct,
doi = {10.1021/acsnano.6c07706},
url = {https://europepmc.org/article/MED/42915643},
note = {CC BY},
}
RIS
TY - JOUR
TI - Inositol Hexakisphosphate Promotes Open Pore State in HIV Capsid Protein Lattice by Reconfiguring Subunit Contacts.
AU - Yari Katar Knelissen
AU - Judith Escrig
AU - Amanda C Macke
AU - Sruthi Sudhakar
AU - Santos Domínguez-Zotes
AU - Sourav Maity
AU - Mauricio G Mateu
AU - Juan R Perilla
AU - Wouter H Roos
AU - Alejandro Valbuena
PY - 2026
DA - 2026/10/01
JO - ACS nano
DO - 10.1021/acsnano.6c07706
UR - https://europepmc.org/article/MED/42915643
AB - The mature human immunodeficiency virus (HIV-1) capsid is composed of approximately 250 capsid protein hexamers, each containing a central pore delimited by a β-hairpin and an α-helix from each monomer. The cellular metabolite inositol hexakisphosphate (IP6) binds this pore and modulates translocation of nucleoside triphosphates into the capsid, where they fuel reverse transcription of the viral genome. However, the mechanism by which IP6 modulates the pore conformation is poorly understood. Averaged structural models of the HIV-1 capsid protein lattice have shed some light on this mechanism but lack information on the dynamic behavior of individual hexamers that could provide deeper mechanistic insights. Here we visualized in real time by high-speed atomic force microscopy the asynchronous motions of individual hexamer pores in the presence or absence of IP6, identifying dynamic transitions between two major states. Quantitative analysis enabled estimation of the IP6-induced pore conformations and populations. Constant-pH molecular dynamics simulations further reveal that IP6 induces contact rewiring at the pore entrance, stabilizing the open state through coordinated rearrangement of intersubunit interactions. Consistently, mechanical fatigue assays show that IP6 markedly enhances the resistance of the capsid lattice to mechanical fatigue, revealing its role as a mechanically stabilized nanomaterial. Together, these results establish IP6 as a proviral regulator that couples nanoscale pore dynamics, intersubunit contact reconfiguration, and mechanical resilience of the HIV-1 capsid, providing a unified mechanistic framework for its role in viral replication.
SN - 1936-0851
SN - 1936-086X
ER -