3F9K: Two Domain Fragment Of Hiv-2 Integrase In Complex With Ledgf Ibd

Citation:
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.
PDB ID: 3F9KDownload
MMDB ID: 69187
PDB Deposition Date: 2008/11/14
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 3.2  Å
Source Organism:
Human immunodeficiency virus type 2 (ISOLATE ROD)
Similar Structures:
Biological Unit for 3F9K: trimeric; determined by author and by software (PQS)
Molecular Components in 3F9K
Label Count Molecule
Proteins (3 molecules)
2
Integrase
Molecule annotation
1
PC4 and Sfrs1-interacting Protein(Gene symbol: PSIP1)
Molecule annotation
Chemicals (4 molecules)
1
2
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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