29ql | pdb_000029ql

FKBP12 in complex with bifunctional ligand a1d and the second bromodomain of BRD4

spinqualitylabelsall models 29ql, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 29ql is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: A1JAZ, MES Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. Function BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed 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. Cell type-selective targeting by heterobifunctional protein binders via in-cell enrichment.,Bulldan A, Zheng M, Meyners C, Purder PL, Krieger J, Dreizler JK, Geiger TM, Repity ML, Lein MH, Quist-Lokken I, Tewes N, Smith ER, Schwab K, Fischer M, Schwalm MP, Dey R, Aswathaman Sivashanmugam S, Schlesiger S, Moniot S, Knapp S, Hartung IV, Holien T, Loewer A, Hausch F Nat Commun. 2026 Sep 17;17(1):9929. doi: 10.1038/s41467-026-77460-w. PMID:42754590 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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