PDBsum entry 6tlc

Transcription

PDB id: 6tlc

Contents

Protein chains

535 a.a.

95 a.a.

Waters ×2

PDB id:

6tlc

Name:

Transcription

Title:

Unphosphorylated human stat3 in complex with ms3-6 monobody

Structure:

Signal transducer and activator of transcription 3. Chain: b, a. Synonym: acute-phase response factor. Engineered: yes. Monobody. Chain: d, c. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: stat3, aprf. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

2.90Å R-factor: 0.248 R-free: 0.281

Authors:

G.La Sala,K.Lau,A.Reynaud,F.Pojer,O.Hantschel

Key ref:

G.La Sala et al. (2020). Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains. Nat Commun, 11, 4115. PubMed id: 32807795 DOI: 10.1038/s41467-020-17920-z

Date:

02-Dec-19 Release date: 22-Jul-20

Protein chains

P40763  (STAT3_HUMAN) -  Signal transducer and activator of transcription 3 from Homo sapiens

Seq: 770 a.a.

Struc: 535 a.a.

Protein chains

No UniProt id for this chain

Struc: 95 a.a.

DOI no: 10.1038/s41467-020-17920-z

Nat Commun 11:4115 (2020)

PubMed id: 32807795

Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.

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.

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.