HIV-1 integrase on the LEDGF IBD: the same pocket as KMT2A, a thousandfold tighter, and a published competition that displaces the leukaemic complex at IC50 301 nM
also called IN-LEDGF · integrase IBD · 2B4J · LEDGF selectivity
The part of LEDGF that grips KMT2A is the same part HIV's integrase grips, and integrase grips it about a thousand times harder. Adding integrase to the leukaemic complex pulls LEDGF off it - which is both the clearest proof the pocket can be drugged and the reason a drug for it will be hard to make selective.
The same thing, for a scientist
The LEDGF/p75 IBD is the docking site for HIV-1 integrase, defined at 2.02 A in PDB 2B4J. Murai et al. show that the integrase footprint on the IBD overlaps the KMT2A IBM2 site specifically - integrase Trp131 occupies the position taken by KMT2A Phe148 - and that because integrase binds the IBD roughly two orders of magnitude more tightly (quoted Kd about 10 nM) than the menin-MLL complex does (1.4 uM), integrase sequesters the IBD from the ternary complex, disrupting it with IC50 = 301 nM in AlphaLISA. This is the only published demonstration that the LEDGF-KMT2A grip can be broken by a competing ligand, and it is simultaneously the sharpest statement of the selectivity problem: the target site is a validated antiviral site with a decade of allosteric integrase-inhibitor chemistry aimed at the opposite side of the same interaction.
One pocket, two diseases, opposite directions
An antiviral programme wants to block integrase from using the IBD. A leukaemia programme wants to block KMT2A from using the same IBD. Both are displacement problems at the same surface, but the ligand they must beat differs by a factor of about 140 in affinity (10 nM against 1.4 uM), so the potency requirement is very different - and a compound optimised for one is not automatically useful for the other.
The existing LEDGF-derived allosteric integrase inhibitors (LEDGINs) bind integrase, not the IBD, so they do not transfer. The graph's target-phase2-psip1-ibd-dossier records three potent ChEMBL rows against PSIP1 from HIV antiviral chemistry with a best IC50 of 470 nM; this entry supplies the structural reason those rows exist and why the chemistry points away from oncology.
What the competition experiment does and does not show
It shows that a protein ligand can evict the IBD from a preassembled menin-MLL-LEDGF complex in a biochemical assay, with a measured IC50 1. It does not show that the complex can be broken in cells, that breaking it is sufficient to kill leukaemia cells, or that a small molecule can achieve the same thing. Its value is as a positive control for druggability: the interaction is displaceable, which is not true of every protein-protein interface in this graph.
| partner a | gene-psip1 |
|---|---|
| partner b | HIV-1 integrase (not a node in this graph) |
| motif a | LEDGF/PSIP1 integrase-binding domain (IBD), the same surface that receives KMT2A IBM2 |
| motif b | HIV-1 integrase catalytic core domain; Trp131 occupies the position of KMT2A Phe148 |
| kd NM | 10 |
| significance | the only published demonstration that the LEDGF-KMT2A grip can be competed away by another ligand, with a measured IC50 |
| druggability | positive control for displaceability; but the chemistry that exists at this interaction targets integrase rather than the IBD, so it does not transfer to oncology |
| resolution note | PDB metadata fetched from data.rcsb.org 2026-09-20; the citation title used here is the PubMed title, which differs from the title stored in RCSB for the same record |
interface residues a
[ "PSIP1 L363", "PSIP1 I403", "PSIP1 F406" ]
kd measurements
[
{
"ligand": "HIV-1 integrase + LEDGF IBD",
"kd_nM": 10,
"method": "quoted by Murai et al. from prior work",
"source_pmid": "25305204"
},
{
"ligand": "KMT2A-menin complex + LEDGF IBD (comparator)",
"kd_nM": 1400,
"method": "ITC",
"source_pmid": "25305204"
},
{
"ligand": "integrase disrupting IBD-menin-MLL",
"ic50_nM": 301,
"method": "AlphaLISA",
"source_pmid": "25305204"
}
]structures
[ "2B4J", "3HPG" ]
structure details
[
{
"pdb": "2B4J",
"title_fetched": "Structural basis for the recognition between HIV-1 integrase and LEDGF/p75",
"method": "X-ray",
"resolution_A": 2.02,
"fetched": "2026-09-20",
"note": "the PubMed title of the same citation reads 'transcriptional coactivator p75', not 'LEDGF/p75'"
},
{
"pdb": "3HPG",
"title_fetched": "Visna virus integrase (residues 1-219) in complex with LEDGF IBD: examples of open integrase dimer-dimer interfaces",
"method": "X-ray",
"resolution_A": 3.28,
"fetched": "2026-09-20"
}
]- Selectivity: at least four ligands share this IBD surface, and the tightest of them is a viral protein a hundredfold stronger than the leukaemic complex; a ligand tuned to one will not be clean against the others.
- Chemistry mismatch: the existing compounds at this interaction bind integrase, not the IBD, so the apparent chemical matter in databases is pointed the wrong way.
- Assay-to-cell gap: the 301 nM figure is AlphaLISA with recombinant proteins and has never been reproduced as displacement on chromatin.
- Host-factor toxicity: LEDGF is required for H3K36me-directed targeting generally, so full displacement has a broad functional cost.
- Can a small molecule reproduce the 301 nM displacement that integrase achieves as a protein? No compound has been reported against the IBD's MLL-binding face.
- Do POGZ and JPO2 also compete with KMT2A for the IBD at physiological concentrations, and if so is the KMT2A complex ever the dominant occupant?
- Does displacing LEDGF from the fusion in cells phenocopy PSIP1 knockout, which in DepMap is selectively required in KMT2A-rearranged lines?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
HIV-1 integrase and the KMT2A IBM2 motif use overlapping surfaces on the LEDGF IBD - integrase Trp131 occupies the site of KMT2A Phe148 - and integrase disrupts the IBD-menin-MLL interaction with IC50 301 nM in AlphaLISA, consistent with its roughly hundredfold tighter IBD affinity.
The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. · Murai MJ, Pollock J, He S, et al. · Blood 2014What this evidence cannot show
A biochemical competition assay with recombinant proteins; the integrase Kd of about 10 nM is quoted by Murai et al. from an earlier study rather than measured in this work. No cellular displacement experiment is reported. Full text reached by the PMC HTML route after fullTextXML returned HTTP 500.
Evidence that argues against this (1)
- The IBD is used mutually exclusively by several cellular partners besides KMT2A - POGZ and JPO2 among them - so a displacement that looks selective for the leukaemic complex in a two-component assay need not be selective in a nucleus. Cherepanov P et al. 2005
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
The structural basis of HIV-1 integrase recognition by the LEDGF/p75 IBD is defined at 2.02 A in PDB 2B4J.
Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. · Cherepanov P, Ambrosio AL, Rahman S, et al. · Proc Natl Acad Sci U S A 2005What this evidence cannot show
An integrase catalytic-core-domain construct with the isolated IBD; the paper is about virology and says nothing about KMT2A. Its PubMed title ('transcriptional coactivator p75') differs from the title RCSB stores for the same citation ('LEDGF/p75'), which is exactly the kind of near-miss that produces a wrong stored title - the PubMed title is used here.
Evidence that argues against this (1)
- A lentiviral integrase-IBD crystal from a different virus (3HPG, visna virus, 3.28 A) shows the same IBD surface engaged in a different dimer-dimer arrangement, so the IBD's integrase-binding mode is not unique even within the retroviral literature. Cherepanov P et al. 2005
the IBD surface shared with KMT2A IBM2
integrase occupies the IBM2 site and displaces the menin-MLL complex, IC50 301 nM
the structural reason the only ChEMBL rows against PSIP1 come from antiviral chemistry
the selectivity liability that entry names, with the structure and the IC50
corrects what the HIV chemistry on this interface actually targets