4EQ1

Crystal Structure of the ARNT PAS-B homodimer

Summary for 4EQ1

• Entry DOI: 10.2210/pdb4eq1/pdb
• Related: 1X0O 2B02 2HV1 2K7S 3F1N 3F1O 3F1P 3H7W 3H82
• Descriptor: Aryl hydrocarbon receptor nuclear translocator, 3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL (3 entities in total)
• Functional Keywords: per-arnt-sim, transcription regulation, homodimer, transcription factor, dna-binding, hif1, hif2, ahr, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P27540
• Total number of polymer chains: 2
• Total formula weight: 26099.60

Authors

Gardner, K.H.,Key, J.M. (deposition date: 2012-04-17, release date: 2013-04-17, Last modification date: 2023-09-13)

Primary citation

Guo, Y.,Partch, C.L.,Key, J.,Card, P.B.,Pashkov, V.,Patel, A.,Bruick, R.K.,Wurdak, H.,Gardner, K.H.
Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules.
Acs Chem.Biol., 8:626-635, 2013

PubMed Abstract: For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator. In one route, we used in vitro NMR and biochemical screening to identify small molecules that selectively bind within the ARNT PAS (Per-ARNT-Sim) domain that recruits TACC3, identifying KG-548 as an ARNT/TACC3 disruptor. A parallel, cell-based screening approach previously implicated the small molecule KHS101 as an inhibitor of TACC3 signaling. Here, we show that KHS101 works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1α. Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors.

PubMed: 23240775
DOI: 10.1021/cb300604u

Experimental method

X-RAY DIFFRACTION (1.6 Å)