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Understanding p300-transcription factor interactions using sequence variation and hybridization

DOI: 10.1039/D2CB00026A DOI Help

Authors: Fruzsina Hóbor (University of Leeds) , Zsofia Hegedus (University of Leeds) , Amaurys Avila Ibarra (University of Bristol) , Vencel L. Petrovicz (University of Szeged) , Gail J. Bartlett (University of Bristol,) , Richard B. Sessions (University of Bristol) , Andrew J. Wilson (University of Leeds) , Thomas A. Edwards (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Rsc Chemical Biology , VOL 105

State: Published (Approved)
Published: April 2022
Diamond Proposal Number(s): 19248

Open Access Open Access

Abstract: The hypoxic response is central to cell function and plays a significant role in the growth and survival of solid tumours. HIF-1 regulates the hypoxic response by activating over 100 genes responsible for adaptation to hypoxia, making it a potential target for anticancer drug discovery. Although there is significant structural and mechanistic understanding of the interaction between HIF-1α and p300 alongside negative regulators of HIF-1α such as CITED2, there remains a need to further understand the sequence determinants of binding. In this work we use a combination of protein expression, chemical synthesis, fluorescence anisotropy and isothermal titration calorimetry for HIF-1α sequence variants and a HIF-1α-CITED hybrid sequence which we term CITIF. We show the HIF-1α sequence is highly tolerant to sequence variation through reduced enthalpic and less unfavourable entropic contributions, These data imply backbone as opposed to side chain interactions and ligand folding control the binding interaction and that sequence variations are tolerated as a result of adopting a more disordered bound interaction or “fuzzy” complex.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography

Added On: 28/04/2022 09:03


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)