7QGS

Crystal structure of p300 CH1 domain in complex with CITIF (a CITED2-HIF-1alpha hybrid)

Summary for 7QGS

• Entry DOI: 10.2210/pdb7qgs/pdb
• Descriptor: Cbp/p300-interacting transactivator 2,Hypoxia-inducible factor 1-alpha, Histone acetyltransferase, ZINC ION, ... (4 entities in total)
• Functional Keywords: hypoxia, transcription factor, intrinsically disordered protein, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 17491.15

Authors

Hegedus, Z.,Wilson, A.J.,Edwards, T.A. (deposition date: 2021-12-10, release date: 2022-05-11, Last modification date: 2024-01-31)

Primary citation

Hobor, F.,Hegedus, Z.,Ibarra, A.A.,Petrovicz, V.L.,Bartlett, G.J.,Sessions, R.B.,Wilson, A.J.,Edwards, T.A.
Understanding p300-transcription factor interactions using sequence variation and hybridization.
Rsc Chem Biol, 3:592-603, 2022

PubMed 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.

PubMed: 35656479
DOI: 10.1039/d2cb00026a

Experimental method

X-RAY DIFFRACTION (2 Å)