9PFO

Structure of POU2F3 POU domains bound to coactivator OCA-T2 and DNA (2.1 angstrom resolution)

Summary for 9PFO

• Entry DOI: 10.2210/pdb9pfo/pdb
• Related: 1CQT 1OCT 9PFN 9PFP
• Descriptor: POU domain, class 2, transcription factor 3, POU class 2 homeobox associating factor 3, DNA containing POU domain recognition element octamer (sense strand), ... (5 entities in total)
• Functional Keywords: transcription factor, dna binding, coactivator complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 16
• Total formula weight: 127592.08

Authors

Ipsaro, J.J.,Alpsoy, A.,Vakoc, C.R.,Joshua-Tor, L. (deposition date: 2025-07-06, release date: 2025-10-01, Last modification date: 2025-12-03)

Primary citation

Alpsoy, A.,Ipsaro, J.J.,Skopelitis, D.,Pal, S.,Chung, F.S.,Carpenter, S.,Desmarais, J.J.,Wu, X.S.,Chang, K.,DiMare, M.T.,Harten, E.,Bergman, S.,Kinney, J.B.,Engelman, J.A.,Bhang, H.C.,Joshua-Tor, L.,Vakoc, C.R.
Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3.
Cell Rep, :116572-116572, 2025

PubMed Abstract: The transcription factor POU2F3 defines the identity of tuft cells and underlies a distinct molecular subtype of small cell lung cancer (SCLC). Although POU2F3 is considered undruggable, its activity critically depends on the coactivators OCA-T1 and OCA-T2. Here, we demonstrate that acute suppression of either POU2F3 or OCA-T1 induces regression of tuft cell-like SCLC xenografts in vivo. To explore the structural basis and druggability of this dependency, we determine crystal structures of POU2F3 bound to OCA-T1 or OCA-T2 in complex with DNA, revealing a tripartite, DNA-dependent interface. We further employ deep mutational scanning to assess the functional impact of 4,218 missense variants in POU2F3 and OCA-T1, uncovering both mutation-sensitive hotspots and structurally constrained regions critical for tumor cell fitness. These findings define a transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3-OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.

PubMed: 41260223
DOI: 10.1016/j.celrep.2025.116572

Experimental method

X-RAY DIFFRACTION (2.1 Å)