Structure of the HIV-1 Nucleocapsid Protein Bound to the SL3 Ψ-RNA Recognition Element
Abstract
The three-dimensional structure of the human immunodeficiency virus–type 1 (HIV-1) nucleocapsid protein (NC) bound to the SL3 stem-loop recognition element of the genomic Ψ RNA packaging signal has been determined by heteronuclear magnetic resonance spectroscopy. Tight binding (dissociation constant, ∼100 nM) is mediated by specific interactions between the amino- and carboxyl-terminal CCHC-type zinc knuckles of the NC protein and the G 7 and G 9 nucleotide bases, respectively, of the G 6 -G 7 -A 8 -G 9 RNA tetraloop. A 8 packs against the amino-terminal knuckle and forms a hydrogen bond with conserved Arg 32 , and residues Lys 3 to Arg 10 of NC form a 3 10 helix that binds to the major groove of the RNA stem and also packs against the amino-terminal zinc knuckle. The structure provides insights into the mechanism of viral genome recognition, explains extensive amino acid conservation within NC, and serves as a basis for the development of inhibitors designed to interfere with genome encapsidation.
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Full-length Gag preferentially binds to a G//AGG loop in SL1, rather than the GGAG tetraloop in SL3.
“the full-length Gag was shown to preferentially bind to a G//AGG loop in SL1, rather than the GGAG tetraloop in SL3”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as De Guzman et al. 1998
In HIV-1, HIV-2, HTLV-1, SIV, MMTV, and MPMV, single-stranded purine or unpaired stretches are critical for gRNA packaging, with mutational disruption leading to impaired Gag binding and gRNA packaging.
“in HIV-1, HIV-2, HTLV-1, SIV, MMTV, and MPMV, single-stranded purine or unpaired stretches are critical for gRNA packaging, with mutational disruption leading to impaired Gag binding and gRNA packaging”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as De Guzman et al. 1998
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Clever, J., Sassetti, C., & Parslow, T. G. (1995) · Journal of Virology · doi:10.1128/jvi.69.4.2101-2109.1995 · Cited by 307 · see citing works
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HIV-1 Gag proteins: diverse functions in the virus life cycle
Freed, E. O. (1998) · Virology · doi:10.1006/viro.1998.9398 · Cited by 717 · see citing works
How retroviruses select their genomes
D'Souza, V., & Summers, M. F. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1210 · Cited by 339 · see citing works
Self-citationSequence-specific binding of single-stranded RNA: is there a code for recognition?
Auweter, S. D., Oberstrass, F. C., & Allain, F. H.-T. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl620 · Cited by 314 · see citing works
On the Role of the SP1 Domain in HIV-1 Particle Assembly: a Molecular Switch?
Datta, S. A. K., Temeselew, L. G., Crist, R. M., Soheilian, F., Kamata, A., Mirro, J., Harvin, D., Nagashima, K., Cachau, R. E., & Rein, A. (2011) · Journal of Virology · doi:10.1128/jvi.00006-11 · Cited by 127 · see citing works
Lever, A. M. L. (2007) · Advances in Pharmacology · doi:10.1016/s1054-3589(07)55001-5 · Cited by 103 · see citing works
Pillai, V. N., Ali, L. M., Prabhu, S. G., Krishnan, A., Tariq, S., Mustafa, F., & Rizvi, T. A. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e12892 · Cited by 4 · see citing works
Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication
Jehad, M. A., Ali, L. M., Pillai, V. N., Prabhu, S. G., Mustafa, F., & Rizvi, T. A. (2026) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaf066 · Cited by 5 · see citing works
“…purine or unpaired stretches are critical for gRNA packaging, with mutational disruption leading to impaired Gag binding and gRNA packaging (De Guzman et al. 1998 , Baig et al. 2009 , Abd El-Wahab et al. 2014 , Keane et al. 2015 , Keane and Summers 2016 , Comas-Garcia et al. 2018 , Singh…”
- Authors
- De Guzman, R. N., Wu, Z. R., Stalling, C. C., Pappalardo, L., Borer, P. N., & Summers, M. F.
- Affiliations
- R. N. De Guzman, Z. R. Wu, C. C. Stalling, M. F. Summers, Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Maryland–Baltimore County (UMBC), 1000 Hilltop Circle, Baltimore, MD 21250, USA.
- Howard Hughes Medical Institute (US)
- Corresponding author
- Borer, Philip N.
- Summers, Michael F.
- Venue
- Science
- Published
- 1998-01-16
- Volume
- 279
- Issue
- 5349
- Pages
- 384-388
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2158977548
- Cited by
- 659
- References
- 1
- Citations by year
- 2026: 13 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 18 · 2021: 19 · 2020: 24 · 2019: 14 · 2018: 25 · 2017: 16 · 2016: 13 · 2015: 16 · 2014: 24 · 2013: 29 · 2012: 32
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM032691, GM-42561, GM32691)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- HIV-1 nucleocapsid protein, RNA tetraloop, protein-RNA complex structure, genome encapsidation, 310-helix, HIV-1 reverse transcriptase inhibitors
- MeSH terms
- Amino Acid Sequence, Base Sequence, Binding Sites, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Nucleic Acid Conformation, Protein Conformation, RNA, Viral, Zinc, HIV-1, Gene Products, gag, Zinc Fingers, Genome, Viral, Protein Structure, Secondary, Protein Folding, Nucleocapsid
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