Summary information and primary citation
- PDB-id
-
9pfo;
DSSR-derived features in text and
JSON formats; DNAproDB
- Class
- transcription
- Method
- X-ray (2.1 Å)
- Summary
- Structure of pou2f3 pou domains bound to coactivator
oca-t2 and DNA (2.1 angstrom resolution)
- Reference
-
Alpsoy A, Ipsaro JJ, Skopelitis D, Pal S, Chung FS,
Carpenter S, Desmarais JJ, Wu XS, Chang K, DiMare MT,
Harten E, Bergman S, Kinney JB, Engelman JA, Bhang HC,
Joshua-Tor L, Vakoc CR (2025): "Structural
basis of DNA-dependent coactivator recruitment by the
tuft cell master regulator POU2F3." Cell
Rep, 44, 116572. doi: 10.1016/j.celrep.2025.116572.
- 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.
