3H82

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains with the artificial ligand THS020

3H82 の概要

• エントリーDOI: 10.2210/pdb3h82/pdb
• 関連するPDBエントリー: 1P97 1X0O 2A24 2B02 3F1N 3F1O 3F1P 3H7W
• 分子名称: Aryl hydrocarbon receptor nuclear translocator, Endothelial PAS domain-containing protein 1, N-(furan-2-ylmethyl)-2-nitro-4-(trifluoromethyl)aniline, ... (4 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus (Potential): P27540; Nucleus: Q99814
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28067.60

構造登録者

Key, J.M.,Scheuermann, T.H.,Anderson, P.C.,Daggett, V.,Gardner, K.H. (登録日: 2009-04-28, 公開日: 2010-01-12, 最終更新日: 2023-09-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.5 Å)