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Updated: Mar 12, 2026

Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 15, 2010
Dynamic conformational changes in the rhesus TRIM5α dimer dictate the potency of HIV-1 restriction
Rajan Lamichhane1, Santanu Mukherjee2, Nikolai Smolin3
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Abstract:
The TRIM5α protein from rhesus macaques (rhTRIM5α) mediates a potent inhibition of HIV-1 infection via a mechanism that involves the abortive disassembly of the viral core. We have demonstrated that alpha-helical elements within the Linker 2 (L2) region, which lies between the SPRY domain and the Coiled-Coil domain, influence the potency of restriction. Here, we utilize single-molecule FRET analysis to reveal that the L2 region of the TRIM5α dimer undergoes dynamic conformational changes, which results in the displacement of L2 regions by 25 angstroms relative to each other. Analysis of restriction enhancing or abrogating mutations in the L2 region reveal that restriction defective mutants are unable to undergo dynamic conformational changes and do not assume compact, alpha-helical conformations in the L2 region. These data suggest a model in which conformational changes in the L2 region mediate displacement of CA bound SPRY domains to induce the destabilization of assembled capsid during restriction.
Insights
Rhesus TRIM-alpha5 (rhTRIM5α) protein restricts HIV-1 by destabilizing the viral core. Dynamic conformational changes in its L2 region are crucial for this antiviral restriction mechanism.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- The TRIM5α protein from rhesus macaques (rhTRIM5α) inhibits HIV-1 infection.
- This inhibition involves the premature disassembly of the viral core.
- Alpha-helical elements in the Linker 2 (L2) region of TRIM5α affect its restriction potency.
Purpose of the Study:
- To investigate the dynamic conformational changes in the L2 region of rhTRIM5α.
- To understand the role of these conformational changes in HIV-1 restriction.
Main Methods:
- Single-molecule Förster Resonance Energy Transfer (smFRET) analysis.
- Analysis of restriction-modulating mutations in the L2 region.
Main Results:
- The L2 region of rhTRIM5α dimers undergoes dynamic conformational changes, displacing L2 regions by 25 angstroms.
- Mutations that impair restriction prevent these dynamic changes and stable alpha-helical conformations in the L2 region.
Conclusions:
- Conformational changes in the L2 region are essential for rhTRIM5α's antiviral activity.
- These changes likely mediate the displacement of SPRY domains, leading to capsid destabilization and HIV-1 restriction.
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