4QL1

Crystal structure of human WDR5 in complex with compound OICR-9429

Summary for 4QL1

• Entry DOI: 10.2210/pdb4ql1/pdb
• Descriptor: WD repeat-containing protein 5, N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide, UNKNOWN ATOM OR ION, ... (6 entities in total)
• Functional Keywords: wdr5, wd repeat domain 5, oicr-9429 inhibitor, structural genomics, structural genomics consortium, sgc, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P61964
• Total number of polymer chains: 2
• Total formula weight: 69845.12

Authors

Dong, A.,Dombrovski, L.,Walker, J.R.,Getlik, M.,Kuznetsova, E.,Smil, D.,Barsyte, D.,Li, F.,Poda, G.,Senisterra, G.,Marcellus, R.,Al-Awar, R.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Schapira, M.,Vedadi, M.,Wu, H.,Structural Genomics Consortium (SGC) (deposition date: 2014-06-10, release date: 2014-12-17, Last modification date: 2023-09-20)

Primary citation

Grebien, F.,Vedadi, M.,Getlik, M.,Giambruno, R.,Grover, A.,Avellino, R.,Skucha, A.,Vittori, S.,Kuznetsova, E.,Smil, D.,Barsyte-Lovejoy, D.,Li, F.,Poda, G.,Schapira, M.,Wu, H.,Dong, A.,Senisterra, G.,Stukalov, A.,Huber, K.V.,Schonegger, A.,Marcellus, R.,Bilban, M.,Bock, C.,Brown, P.J.,Zuber, J.,Bennett, K.L.,Al-Awar, R.,Delwel, R.,Nerlov, C.,Arrowsmith, C.H.,Superti-Furga, G.
Pharmacological targeting of the Wdr5-MLL interaction in C/EBP alpha N-terminal leukemia.
Nat.Chem.Biol., 11:571-578, 2015

PubMed Abstract: The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.

PubMed: 26167872
DOI: 10.1038/nchembio.1859

Experimental method

X-RAY DIFFRACTION (1.5 Å)