3H7W

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains with the artificial ligand THS017

Summary for 3H7W

• Entry DOI: 10.2210/pdb3h7w/pdb
• Related: 1P97 1X0O 2A24 2B02 3H82 3f1n 3f1o 3f1p
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, 2-nitro-N-(thiophen-3-ylmethyl)-4-(trifluoromethyl)aniline, ... (4 entities in total)
• Functional Keywords: pas domain, heterodimer, protein ligand complex., activator, angiogenesis, congenital erythrocytosis, developmental protein, differentiation, disease mutation, dna-binding, hydroxylation, nucleus, phosphoprotein, transcription, transcription regulation, ubl conjugation, alternative splicing, polymorphism
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus (Potential): Q99814; Nucleus: P27540
• Total number of polymer chains: 2
• Total formula weight: 28083.67

Authors

Key, J.M.,Scheuermann, T.H.,Anderson, P.C.,Daggett, V.,Gardner, K.H. (deposition date: 2009-04-28, release date: 2010-01-12, Last modification date: 2023-09-06)

Primary citation

Key, J.,Scheuermann, T.H.,Anderson, P.C.,Daggett, V.,Gardner, K.H.
Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B
J.Am.Chem.Soc., 131:17647-17654, 2009

PubMed Abstract: Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors responsible for the metazoan hypoxia response and promote tumor growth, metastasis, and resistance to cancer treatment. The C-terminal Per-ARNT-Sim (PAS) domain of HIF2alpha (HIF2alpha PAS-B) contains a preformed solvent-inaccessible cavity that binds artificial ligands that allosterically perturb the formation of the HIF heterodimer. To better understand how small molecules bind within this domain, we examined the structures and equilibrium and transition-state thermodynamics of HIF2alpha PAS-B with several artificial ligands using isothermal titration calorimetry, NMR exchange spectroscopy, and X-ray crystallography. Rapid association rates reveal that ligand binding is not dependent upon a slow conformational change in the protein to permit ligand access, despite the closed conformation observed in the NMR and crystal structures. Compensating enthalpic and entropic contributions to the thermodynamic barrier for ligand binding suggest a binding-competent transition state characterized by increased structural disorder. Finally, molecular dynamics simulations reveal conversion between open and closed conformations of the protein and pathways of ligand entry into the binding pocket.

PubMed: 19950993
DOI: 10.1021/ja9073062

Experimental method

X-RAY DIFFRACTION (1.65 Å)