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Protein Purification-free Method of Binding Affinity Determination by Microscale Thermophoresis
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Structural exploration with AlphaFold2-generated STAT3α structure reveals selective elements in STAT3α-GRIM-19
Seema Mishra1, Santosh Kumar2, Kesaban Sankar Roy Choudhuri2
1Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India. seema_uoh@yahoo.com.
Scientific Reports
|December 1, 2021
Summary
GRIM-19 inhibits STAT3 (Signal Transducer and Activator of Transcription 3) by binding to its N-terminal domain (NTD), offering a potential anti-cancer therapy. This study reveals novel structural insights into their interaction, crucial for understanding cancer progression.
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Research
Background:
- Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor constitutively activated in many cancers.
- GRIM-19 is known to bind STAT3 and inhibit its gene expression, making it a potential anti-cancer therapeutic target.
- Previous studies identified STAT3-GRIM-19 binding domains with discrepancies, and the human complex has not been crystallized.
Purpose of the Study:
- To elucidate the structural basis of STAT3α-GRIM-19 binding and interactions.
- To understand the negative regulatory mechanisms of GRIM-19 on STAT3.
- To investigate the binding of GRIM-19 to monomeric and dimeric forms of STAT3α.
Main Methods:
- Homology modeling and ab-initio modeling using I-TASSER and AlphaFold2 to generate STAT3α structures.
- Molecular Dynamics (MD) studies to verify complex stability.
- Analysis of binding affinity and stability through free energy changes upon mutation.
Main Results:
- GRIM-19's N-terminal domain (NTD) binds most strongly to STAT3α's NTD in both unphosphorylated and phosphorylated states, contrasting previous findings.
- Key arginine residues (57, 58, 68) in GRIM-19 are crucial for hydrogen-bonded interactions.
- Mutations Y33P and Q61L in GRIM-19, and R68P and R57M, were identified as major and minor disruptors of binding, respectively.
Conclusions:
- This study provides a novel structural perspective on STAT3α-GRIM-19 binding and inhibition mechanisms.
- GRIM-19 plays a significant role in the formation of the STAT3-GRIM-19 complex.
- The findings offer a basis for developing GRIM-19 as an anti-cancer therapeutic agent.
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