3F9K

Two domain fragment of HIV-2 integrase in complex with LEDGF IBD

Summary for 3F9K

• Entry DOI: 10.2210/pdb3f9k/pdb
• Related: 1K6Y 2B4J
• Descriptor: Integrase, PC4 and SFRS1-interacting protein, ZINC ION, ... (4 entities in total)
• Functional Keywords: protein-protein complex, aids, dna integration, endonuclease, magnesium, metal-binding, multifunctional enzyme, nuclease, nucleotidyltransferase, nucleus, transferase, viral nucleoprotein, virion, dna-binding, host-virus interaction, transcription, transcription regulation, zinc binding, hhcc motif, viral protein, recombination
• Biological source: Human immunodeficiency virus type 2 (HIV-2); More
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04584; Nucleus: O75475
• Total number of polymer chains: 36
• Total formula weight: 703193.57

Authors

Hare, S.,Cherepanov, P. (deposition date: 2008-11-14, release date: 2009-01-20, Last modification date: 2023-11-01)

Primary citation

Hare, S.,Shun, M.C.,Gupta, S.S.,Valkov, E.,Engelman, A.,Cherepanov, P.
A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75
Plos Pathog., 5:e1000259-e1000259, 2009

PubMed Abstract: 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.

PubMed: 19132083
DOI: 10.1371/journal.ppat.1000259

Experimental method

X-RAY DIFFRACTION (3.2 Å)