3h82

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

spinqualitylabelsall models 3h82, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3h82 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.5Å Ligands: 020 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ARNT_HUMAN Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B.,Key J, Scheuermann TH, Anderson PC, Daggett V, Gardner KH J Am Chem Soc. 2009 Dec 9;131(48):17647-54. PMID:19950993 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Factor inhibiting HIF 3D structures of hypoxia-inducible factor

Proteopedia Page Contributors and Editors (what is this?)

OCA