Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel–Lindau SuppressorClick to copy article linkArticle link copied!
- Carmen Domene
- Christian Jorgensen
- Kenno Vanommeslaeghe
- Christopher J. Schofield
- Alexander MacKerell, Jr.
Abstract
The hypoxia-inducible transcription factors (HIF) play a central role in the human oxygen sensing signaling pathway. The binding of the von Hippel–Lindau tumor suppressor protein (pVHL)–ElonginC–ElonginB complex (VCB) to HIF-1α is highly selective for the trans-4-hydroxylation form of when Pro564 in the C-terminal oxygen-dependent degradation domain (ODDD) of HIF-1α. The binding of HIFα for VCB is increased by ∼1000-fold upon addition of a single hydroxyl group to either of two conserved proline-residues. Here, we address how this addition governs selective recognition and characterizes the strength of the interaction of this “switch-like” signaling event. A new set of molecular mechanics parameters for 4-hydroxyproline has been developed following the CHARMM force field philosophy. Using the free energy perturbation (FEP) formalism, the difference in the binding free energies between HIF-1α in the nonhydroxylated and hydroxylated forms with the VCB complex was estimated using over 3 μs of MD trajectories. These results can favorably be compared to an experimental value of ∼4 kcal mol–1. It is observed that the optimized hydrogen bonding network to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. These observations provide insight that will aid in developing therapeutic agents that block HIF-α recognition by pVHL.
Cited By
This article is cited by 1 publications.
- Martine I. Abboud, Tom E. McAllister, Ivanhoe K. H. Leung, Rasheduzzaman Chowdhury, Christian Jorgensen, Carmen Domene, Jasmin Mecinović, Kerstin Lippl, Rebecca L. Hancock, Richard J. Hopkinson, Akane Kawamura, Timothy D. W. Claridge, Christopher J. Schofield. 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2. Chemical Communications 2018, 54
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, 3130-3133. https://doi.org/10.1039/C8CC00387D
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