title: Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 Penn St., Baltimore, Maryland 21201, United States.|Physical & Theoretical Chemistry Laboratory, South Parks Road, University of Oxford , Oxford OX1 3QZ, United Kingdom.
authors.forename: Carmen
authors.initials: C
authors.lastname: Domene
authors.affiliation: Physical & Theoretical Chemistry Laboratory, South Parks Road, University of Oxford , Oxford OX1 3QZ, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 Penn St., Baltimore, Maryland 21201, United States.
authors.forename: Kenno
authors.initials: K
authors.lastname: Vanommeslaeghe
authors.affiliation: Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 Penn St., Baltimore, Maryland 21201, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: MacKerell
mesh_terms: D000075065:Elongin; D006801:Humans; D006900:Hydroxylation; D006909:Hydroxyproline / Q000737:chemistry / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D013816:Thermodynamics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000075065:Elongin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D006909:Hydroxyproline