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Warfarin and vitamin K compete for binding to Phe55 in human VKOR

Nature Structural & Molecular Biology volume 24, pages 77–85 (2017)Cite this article

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Abstract

Vitamin K epoxide reductase (VKOR) catalyzes the reduction of vitamin K quinone and vitamin K 2,3-epoxide, a process essential to sustain γ-carboxylation of vitamin K–dependent proteins. VKOR is also a therapeutic target of warfarin, a treatment for thrombotic disorders. However, the structural and functional basis of vitamin K reduction and the antagonism of warfarin inhibition remain elusive. Here, we identified putative binding sites of both K vitamers and warfarin on human VKOR. The predicted warfarin-binding site was verified by shifted dose–response curves of specified mutated residues. We used CRISPR–Cas9-engineered HEK 293T cells to assess the vitamin K quinone and vitamin K 2,3-epoxide reductase activities of VKOR variants to characterize the vitamin K naphthoquinone head– and isoprenoid side chain–binding regions. Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor.

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Figure 1: Warfarin binding to hVKOR is mediated through a stacking interaction with Phe55 and charge-stabilizing arginine residues.
Figure 2: Mutation-based characterization of in silico–predicted K1- and K1>O-binding residues of hVKOR.
Figure 3: Vitamin K and warfarin share similar binding pockets.
Figure 4: Structural influences of the F55A and F55G variants.
Figure 5: Antagonization of warfarin by vitamin K, on the basis of the FIX activities of HEK 293T wild-type and genetically engineered cells transfected with either F9 cDNA alone or a bicistronic vector containing VKORC1 and F9 cDNA (pIRES VKORC1/F9).
Figure 6: Proposed slow, tight binding mechanism of warfarin to hVKOR.

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Acknowledgements

This work was supported in part by funding from BONFOR (grant 2015-1-01, K.J.C.), Baxter Germany, GmbH (J.O.) and the Deutsche Forschungsgemeinschaft (DFG) (grant Ol100 5-1, M.W. and J.O.). HEK 293T cells were obtained from E. Latz (Institute of Innate Immunity, University Hospitals Bonn; German Center for Neurodegenerative Diseases; and University of Massachusetts Medical School).

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Author notes

  1. Katrin J Czogalla and Arijit Biswas: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

    Katrin J Czogalla, Arijit Biswas, Kerstin Liphardt, Matthias Watzka & Johannes Oldenburg

  2. Institute of Molecular Medicine, University Hospital Bonn, Bonn, Germany

    Klara Höning & Veit Hornung

  3. Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany

    Veit Hornung

  4. Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn, Germany

    Matthias Watzka & Johannes Oldenburg

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  1. Katrin J Czogalla
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Contributions

Experimental design, K.J.C.; data collection, K.J.C. and K.L.; data analysis and figure production, K.J.C., K.L. and A.B.; protein modeling and in silico analysis, A.B.; CRISPR–Cas9 gene editing of HEK 293T cells, K.H., V.H. and K.J.C.; manuscript drafting and editing, K.J.C., A.B., K.H., V.H., K.L., M.W. and J.O.

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Correspondence to Johannes Oldenburg.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Model I and model II of human VKOR.

(a) model-I in cyan with the loop and active site cysteines (yellow).

(b) model-II in blue with the loop and active site cysteines (yellow).

(c) Structural alignment between model-I (cyan) and model-II (blue) focused on the loop area.

Supplementary Figure 2 Docking of K1, K1>O and warfarin on hVKOR models I and II.

(a) illustrates the docking poses resulting from docking of K1 and K1>O on model-I (left and middle) and warfarin on model-II (right).

(b) illustrates the docking poses of K1 and K1>O on model-II (left and middle) and warfarin on model-I (left).

The model backbones are represented in grey ribbon format. The active site and loop cysteines are depicted in blue stick forms. K1, K1>O and warfarin are depicted in stick form with coloring according to the type of atom. The red colored transparent zone indicates location of the favourable docking poses chosen for analysis in this study based on the docking conducted as shown in (b).

Supplementary Figure 3 hVKOR-K1/K1>O residue interaction chart post equilibration (>20 ns).

(a) illustrates the simulation pattern for the K1>O bound structure.

(b) illustrates the simulation pattern for the K1 bound structure.

Both simulations reached equilibration around the 20 ns mark. Data points >20 ns are shown for every 10th simulation snapshot proceeding from 20 ns (i.e. 20 ns, 30 ns,…). The interacting residues for both simulations are similar. The K1 bound structure shows certain additional interacting residues at the end of the simulation (indicated by arrows in (b))

Supplementary Figure 4 Genotypes of VKORC1 and VKORC1L1 single- and double-KO cell lines.

Blue letters highlight target crRNA sequence in the reference sequence, deletions are indicated as dashes, insertions are depicted as extra letters below the sequence.

Supplementary Figure 5 Characterization of vitamin K reductases and NQO1 in VKORC1;VKORC1L1 double-KO cells.

(a) Absolute FIX activities of VKORC1/VKORC1L1 double KO cells transfected with F9 cDNA only (black bars), or F9 together with VKORC1 cDNA (white bars), F9 with VKORC1L1 cDNA (dark grey bars), F9 with NQO1 cDNA (light grey bars). Cells were cultured with different substrates as indicated at the x-achsis (10 μM K1, K1>O, K2, or K2>O).

(b) Absolute FIX activities of VKORC1/VKORC1L1 double KO cells transfected with F9 cDNA. All cells were cultured with 50 μM K1 and different concentrations of warfarin (0 μM, 1 μM, 10 μM) or dicoumarol (0 μM, 1 μM, 10 μM).

Source data

Supplementary Figure 6 Different conformational variations of the Phe55 residue and the ER luminal loop.

Changes within the hydrophobic pocket and the ER luminal loop of hVKOR (grey) at different stages with warfarin and K1>O bound and unbound with respect to the position of the critical residue Phe55 at the base of this pocket. The loop and the active site cysteines are shown in yellow colored stick forms.

(a) Model-I with Phe55 in green

(b) Model-I with warfarin bound (magenta) and Phe55 in red

(c) Model-II with Phe55 in purple

(d) Model-II with K1>O bound (blue) and Phe55 in cyan

(e) comparative view of the orientation of the critical Phe55 residue of all different states

Supplementary Figure 7 Docking of K>O on F55A and F55G variants.

The model backbones are depicted in ribbon format while the ligands are depicted in stick format. The illustration colors are based on secondary structure and atom type.

All depicted models represent simulation averaged equilibrated structures that have been subjected to a membrane embedded simulation run of 150 ns each.

(a) This shows the docking poses for K>O on Ph55Ala variant of the closed loop model-II.

(b) This shows the docking poses for K>O on Ph55Gly variant of the closed loop model-II.

Supplementary Figure 8 Spatial comparison of K1>O-binding residues on hVKOR with other similar complexes.

Comparative spatial location of K1>O binding residues on hVKOR with ubiquinone binding site residues on synVKOR and K1 binding residues on AtVKOR. The residues which are predicted/ known to bind the respective substrate (Yang et al, 2015 and Li et al, 2010) are shown in stick form.

(a) structural alignment of hVKOR model-II (yellow) with a model of the atVKOR (red) [downloaded from Swiss model database (http://swissmodel.expasy.org/repository/; accessed on 29th April 2016)], both in ribbon format.

(b) structural alignment of hVKOR model-II (yellow) with the crystal structure of synVKOR (blue) (PDB ID: 3KP9), both in ribbon format.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1 and 2 (PDF 1453 kb)

Model I structure

The PDB co-ordinates for the VKOR “open” form or Model-I (TXT 205 kb)

PDB file for model II

The PDB co-ordinates for the VKOR “closed” form or Model-II (TXT 205 kb)

Supplementary Data Set 3

Model 1 validation report (PDF 93 kb)

Supplementary Data Set 4

Model 2 validation report (PDF 95 kb)

Simulation of K1–VKOR complex

A video grab of the thermal motion of the K1 ligand within the K1-VKOR complex in a membrane embedded simulation (MOV 30355 kb)

Simulation of K>O–VKOR complex

A video grab of the thermal motion of the K>O ligand within the K>O -VKOR complex in a membrane embedded simulation (MOV 29585 kb)

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Czogalla, K., Biswas, A., Höning, K. et al. Warfarin and vitamin K compete for binding to Phe55 in human VKOR. Nat Struct Mol Biol 24, 77–85 (2017). https://doi.org/10.1038/nsmb.3338

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