ArticlePLoS computational biology2018
Ligand-induced perturbation of the HIF-2α:ARNT dimer dynamics.
Article in PLoS computational biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Examining Genetic Variants Associated with FOXP1 Syndrome through Molecular Dynamics of Its DNA-Binding Domain and Self-Organizing Maps.Journal of chemical information and modeling · 2026Article
- Allosteric Network Analysis Toolkit for Single-Domain Phosphoproteins.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Molecular Dynamics Reveals Altered Interactions between Belzutifan and HIF-2 with Natural Variant G323E or Proximal Phosphorylation at T324.ACS omega · 2024Article
- Review
- TCDD-Induced Allosteric Perturbation of the AhR:ARNT Binding to DNA.International journal of molecular sciences · 2023Article
- SARS-CoV-2 multi-variant rapid detector based on graphene transistor functionalized with an engineered dimeric ACE2 receptor.Nano today · 2023Article
- Identification of oleoylethanolamide as an endogenous ligand for HIF-3α.Nature communications · 2022Article
- Oxygen-sensing mechanisms in development and tissue repair.Development (Cambridge, England) · 2021Review
- Metadynamics-Based Approaches for Modeling the Hypoxia-Inducible Factor 2α Ligand Binding Process.Journal of chemical theory and computation · 2021Article
- Reconstruction of ARNT PAS-B Unfolding Pathways by Steered Molecular Dynamics and Artificial Neural Networks.Journal of chemical theory and computation · 2021Article
- Allosteric Priming of E. coli CheY by the Flagellar Motor Protein FliM.Biophysical journal · 2020Article
- Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form.International journal of molecular sciences · 2020Article
- Insights Into the Binding Mechanism of GC7 to Deoxyhypusine Synthase inFrontiers in chemistry · 2020Article
- Modeling the binding of diverse ligands within the Ah receptor ligand binding domain.Scientific reports · 2019Article
- Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin.Scientific reports · 2019Article
- Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II.PLoS computational biology · 2019Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-α degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-α transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF-α:ARNT dimerization has been proposed as a promising therapeutic strategy. Following the discovery of a druggable cavity within the PAS-B domain of HIF-2α, research efforts have been directed to identify artificial ligands that can impair heterodimerization. Although the crystallographic structures of the HIF-2α:ARNT complex have elucidated the dimer architecture and the 0X3-inhibitor placement within the HIF-2α PAS-B, unveiling the inhibition mechanism requires investigation of how ligand-induced perturbations could dynamically propagate through the structure and affect dimerization. To this end, we compared evolutionary features, intrinsic dynamics and energetic properties of the dimerization interfaces of HIF-2α:ARNT in both the apo and holo forms. Residue conservation analysis highlighted inter-domain connecting elements that have a role in dimerization. Analysis of domain contributions to the dimerization energy demonstrated the importance of bHLH and PAS-A of both partners and of HIF-2α PAS-B domain in dimer stabilization. Among quaternary structure oscillations revealed by Molecular Dynamics simulations, the hinge-bending motion of the ARNT PAS-B domain around the flexible PAS-A/PAS-B linker supports a general model for ARNT dimerization in different heterodimers. Comparison of the HIF-2α:ARNT dynamics in the apo and 0X3-bound forms indicated a model of inhibition where the HIF-2α-PAS-B interfaces are destabilised as a result of water-bridged ligand-protein interactions and these local effects allosterically propagate to perturb the correlated motions of the domains and inter-domain communication. These findings will guide the design of improved inhibitors to contrast cell survival in tumor masses.
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