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A Novel Co-Crystal Structure Affords the Design of Gain-of-Function Lentiviral Integrase Mutants in the Presence of Modified PSIP1/LEDGF/p75
Open accessAbstract
Lens epithelium derived growth factor (LEDGF), also known as PC4 and SFRS1 interacting protein 1 (PSIP1) and transcriptional co-activator p75, is the cellular binding partner of lentiviral integrase (IN) proteins. LEDGF accounts for the characteristic propensity of Lentivirus to integrate within active transcription units and is required for efficient viral replication. We now present a crystal structure containing the N-terminal and catalytic core domains (NTD and CCD) of HIV-2 IN in complex with the IN binding domain (IBD) of LEDGF. The structure extends the known IN-LEDGF interface, elucidating primarily charge-charge interactions between the NTD of IN and the IBD. A constellation of acidic residues on the NTD is characteristic of lentiviral INs, and mutations of the positively charged residues on the IBD severely affect interaction with all lentiviral INs tested. We show that the novel NTD-IBD contacts are critical for stimulation of concerted lentiviral DNA integration by LEDGF in vitro and for its function during the early steps of HIV-1 replication. Furthermore, the new structural details enabled us to engineer a mutant of HIV-1 IN that primarily functions only when presented with a complementary LEDGF mutant. These findings provide structural basis for the high affinity lentiviral IN-LEDGF interaction and pave the way for development of LEDGF-based targeting technologies for gene therapy.
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“Residues Ile356 and Asp366 located on the loop between α-helices 1 and 2 mediate interactions with both IN monomers of the CCD dimer while electropositive residues on the outward face of α-helix 4 interface with electronegative residues of IN NTD α-helix 1 (REF.107,109).”
From Structure and function of retroviral integrase (2022) · cites this paper as [107]
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“The CCD is the main IN binding determinant, with the NTD contributing secondary interactions for full binding affinity106,107.”
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Metadata
- Authors
- Hare, S., Shun, M.-C., Gupta, S. S., Valkov, E., Engelman, A., & Cherepanov, P.
- Affiliations
- Imperial College London (GB)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Engelman, Alan
- Cherepanov, Peter
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-01-09
- Volume
- 5
- Issue
- 1
- Pages
- e1000259
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC2606027
- OpenAlex
- W2032297596
- Cited by
- 166
- References
- 62
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 15 · 2014: 26 · 2013: 11 · 2012: 13
- FWCI
- 12.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- University College London
- European Synchrotron Radiation Facility (ID23‐1)
- National Institutes of Health
- Medical Research Council
- National Institute of Allergy and Infectious Diseases (AI07245, AI70042, AI39394, R01AI039394, R01AI070042, R37AI039394, T32AI007245)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- LEDGF, PSIP1, p75, HIV-1 integrase, crystal structure, gain-of-function mutants, charge-charge interactions, HIV-1 replication
- MeSH terms
- Humans, Mutation, Protein Binding, Transcription Factors, Virus Replication, HIV-2, Lentivirus, Crystallography, X-Ray, HIV Integrase, Adaptor Proteins, Signal Transducing, Human Immunodeficiency Virus Proteins
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