29QL
FKBP12 in complex with bifunctional ligand a1d and the second bromodomain of BRD4
This is a non-PDB format compatible entry.
Summary for 29QL
| Entry DOI | 10.2210/pdb29ql/pdb |
| Descriptor | Bromodomain-containing protein 4, Peptidyl-prolyl cis-trans isomerase FKBP1A, 6-tungstotellurate(VI), ... (6 entities in total) |
| Functional Keywords | complex, inhibitor, bifunctional, isomerase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 60895.69 |
| Authors | |
| Primary citation | Bulldan, A.,Zheng, M.,Meyners, C.,Purder, P.L.,Krieger, J.,Dreizler, J.K.,Geiger, T.M.,Repity, M.L.,Lein, M.H.,Quist-Lokken, I.,Tewes, N.,Smith, E.R.,Schwab, K.,Fischer, M.,Schwalm, M.P.,Dey, R.,Aswathaman Sivashanmugam, S.,Schlesiger, S.,Moniot, S.,Knapp, S.,Hartung, I.V.,Holien, T.,Loewer, A.,Hausch, F. Cell type-selective targeting by heterobifunctional protein binders via in-cell enrichment. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Non-catalytic heterobifunctional protein binders promise to expand the range of therapeutic options by establishing complexes between key target proteins and accessory presenter proteins equipped with additional properties. Here, we systematically investigate the rational design of such molecules, explore the biochemical basis of complex formation and determine how they achieve cellular efficacy using the endogenously expressed immunophilin FKBP12 as presenter protein and the transcriptional regulator BRD4 as target protein. We present classes of bifunctional molecules that enable selective, FKBP12-dependent killing of specific cell types at subnanomolar concentrations and allow to differentiate between closely related bromodomains of the BET family. We propose that the strongly potentiated efficacy of these bifunctional compounds is based on cellular enrichment through binding to the highly abundant presenter protein FKBP12, a mechanism we term "CellTrap". Our findings substantiate the concept that highly expressed, non-essential proteins can be repurposed as selective recruiters to expand therapeutic windows of existing small-molecule inhibitors, opening new avenues for designing targeted drugs with improved cell-type specificity. PubMed: 42754590DOI: 10.1038/s41467-026-77460-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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