4GS9

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with an inactive benzoxadiazole antagonist

Summary for 4GS9

• Entry DOI: 10.2210/pdb4gs9/pdb
• Related: 1P97 1X0O 2A24 2B02 3F1N 3F1O 3F1P 3H7W 3H82 4GHI
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, N-(3-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine, ... (5 entities in total)
• Functional Keywords: pas fold, transcription, protein-protein interactions, nucleus
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q99814 P27540
• Total number of polymer chains: 2
• Total formula weight: 28426.04

Authors

Scheuermann, T.H.,Gardner, K.H. (deposition date: 2012-08-27, release date: 2013-04-03, Last modification date: 2023-09-13)

Primary citation

Rogers, J.L.,Bayeh, L.,Scheuermann, T.H.,Longgood, J.,Key, J.,Naidoo, J.,Melito, L.,Shokri, C.,Frantz, D.E.,Bruick, R.K.,Gardner, K.H.,Macmillan, J.B.,Tambar, U.K.
Development of Inhibitors of the PAS-B Domain of the HIF-2 alpha Transcription Factor
J.Med.Chem., 56:1739-1747, 2013

PubMed Abstract: Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2α-ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.

PubMed: 23363003
DOI: 10.1021/jm301847z

Experimental method

X-RAY DIFFRACTION (1.72 Å)