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PDBsum entry 6tlc
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Transcription
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PDB id
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6tlc
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References listed in PDB file
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Key reference
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Title
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Selective inhibition of stat3 signaling using monobodies targeting the coiled-Coil and n-Terminal domains.
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Authors
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G.La sala,
C.Michiels,
T.Kükenshöner,
T.Brandstoetter,
B.Maurer,
A.Koide,
K.Lau,
F.Pojer,
S.Koide,
V.Sexl,
L.Dumoutier,
O.Hantschel.
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Ref.
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Nat Commun, 2020,
11,
4115.
[DOI no: ]
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PubMed id
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Abstract
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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.
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