6TLC
Unphosphorylated human STAT3 in complex with MS3-6 monobody
Summary for 6TLC
Entry DOI | 10.2210/pdb6tlc/pdb |
Descriptor | Signal transducer and activator of transcription 3, Monobody (3 entities in total) |
Functional Keywords | inhibitor, complex, stat3, monobody, transcription |
Biological source | Homo sapiens (Human) More |
Total number of polymer chains | 4 |
Total formula weight | 156752.86 |
Authors | La Sala, G.,Lau, K.,Reynaud, A.,Pojer, F.,Hantschel, O. (deposition date: 2019-12-02, release date: 2020-07-22, Last modification date: 2024-01-24) |
Primary citation | La Sala, G.,Michiels, C.,Kukenshoner, T.,Brandstoetter, T.,Maurer, B.,Koide, A.,Lau, K.,Pojer, F.,Koide, S.,Sexl, V.,Dumoutier, L.,Hantschel, O. Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains. Nat Commun, 11:4115-4115, 2020 Cited by PubMed Abstract: The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms. PubMed: 32807795DOI: 10.1038/s41467-020-17920-z PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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