5KIZ

Solution Structure of a repacked version of HIF-2 alpha PAS-B

Summary for 5KIZ

• Entry DOI: 10.2210/pdb5kiz/pdb
• NMR Information: BMRB: 30118
• Descriptor: Endothelial PAS domain-containing protein 1 (1 entity in total)
• Functional Keywords: cavity, repacking, rosetta, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 13264.09

Authors

Correa, F.,Key, J.,Kuhlman, B.,Gardner, K.H. (deposition date: 2016-06-17, release date: 2016-08-17, Last modification date: 2024-05-15)

Primary citation

Correa, F.,Key, J.,Kuhlman, B.,Gardner, K.H.
Computational Repacking of HIF-2 alpha Cavity Replaces Water-Based Stabilized Core.
Structure, 24:1918-1927, 2016

PubMed Abstract: Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors central to hypoxia response and cancer development. Within the HIF-2 complex, one domain (HIF-2α PAS-B) contains a large (290 Å) buried cavity filled with water molecules within its hydrophobic core. Such cavities are uncommon except in the case of ligand-binding proteins, leading to the hypothesis that HIF-2α can be regulated by small molecules. The development of artificial HIF-2α inhibitors validates this hypothesis but raises questions about the impact of this cavity on HIF-2α PAS-B structure and function. To answer these points, we used computational methods to construct a repacked protein containing a smaller cavity within the native fold. Experimental validation of a five-mutation variant confirms achieving these objectives and stabilizing the folded structure. Complementary functional data establish that ligands cannot bind this variant although heterodimerization remains unchanged. Altogether, our strategy innovatively addresses the roles of solvated cavities in maintaining protein stability and function.

PubMed: 27667693
DOI: 10.1016/j.str.2016.08.014

Experimental method

SOLUTION NMR