Identification of the functional states of human vitamin K epoxide reductase from molecular dynamics simulations

Chatron, Nolan; Chalmond, Bernard; Trouvé, Alain; Benoît, Etienne; Caruel, Hervé; Lattard, Virginie; Tchertanov, Luba

doi:10.1039/c7ra07463h

Cited by 13 publications

(60 citation statements)

References 74 publications

(101 reference statements)

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“…Modelling the full-length KIT cytoplasmic domain. Progress in computational algorithms and technique has enabled in depth study of protein molecular structure and dynamics using limited experimental data [14][15][16][17] . The model is built based on a known 3D homologous protein structure is at present the widely used approach.…”

Section: Resultsmentioning

confidence: 99%

“…Four candidate models (M1, M2, M3 and M4) of the full-length KIT cytoplasmic domain were explored by all-atoms MD simulations. Since the success of MD simulations over a ten to hundreds of nanoseconds time scale for the refinement of homology or ab initio models of small to medium-size proteins was demonstrated 14,15,17,19 , we expected that the 500-ns MD simulations may be pertinent when scanning a conformational stability of the alternative KIT models. We suggest that such simulation time would allow the equilibrated state of the protein to be reached for a biologically relevant model.…”

Section: Resultsmentioning

confidence: 99%

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The First 3D Model of the Full-Length KIT Cytoplasmic Domain Reveals a New Look for an Old Receptor

Inizan

Hanna

Stolyarchuk

et al. 2020

Sci Rep

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Receptor tyrosine kinases (RTKs) are key regulators of normal cellular processes and have a critical role in the development and progression of many diseases. RTK ligand-induced stimulation leads to activation of the cytoplasmic kinase domain that controls the intracellular signalling. Although the kinase domain of RTKs has been extensively studied using X-ray analysis, the kinase insert domain (KID) and the C-terminal are partially or fully missing in all reported structures. We communicate the first structural model of the full-length RTK KIT cytoplasmic domain, a crucial target for cancer therapy. This model was achieved by integration of ab initio KID and C-terminal probe models into an X-ray structure, and by their further exploration through molecular dynamics (MD) simulation. An extended (2-µs) MD simulation of the proper model provided insight into the structure and conformational dynamics of the full-length cytoplasmic domain of KIT, which can be exploited in the description of the KIT transduction processes. Receptor Tyrosine Kinases (RTKs) are cell-surface transmembrane proteins that control cell-signalling pathways 1 .

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The First 3D Model of the Full-Length KIT Cytoplasmic Domain Reveals a New Look for an Old Receptor

Inizan

Hanna

Stolyarchuk

et al. 2020

Sci Rep

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“…In contrast, highest vkorc1l1 gene expression in vertebrates was found in brain and ovaries, but also high expression levels were reported in organs, like kidney, eye, and testis [ 31 , 56 , 58 ]. Recent structural insights on how VKORC1 is preferentially binding to VK1 and MK4, rather than MK7 [ 69 ] pointed out further differences on VK recycling capacity, depending on the substrate (VK form) and the VKOR paralog (VKORC1 or VKORC1L1). The presence of VK metabolites, γ-carboxylation activity, and VK recycling in male and female gonads might be the first evidence suggesting that VK might be required in vertebrate’s reproduction.…”

Section: Vitamin K Molecular Pathwaysmentioning

confidence: 99%

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

2020

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Vitamin K (VK) is a fat-soluble vitamin that vertebrates have to acquire from the diet, since they are not able to de novo synthesize it. VK has been historically known to be required for the control of blood coagulation, and more recently, bone development and homeostasis. Our understanding of the VK metabolism and the VK-related molecular pathways has been also increased, and the two main VK-related pathways—the pregnane X receptor (PXR) transactivation and the co-factor role on the γ-glutamyl carboxylation of the VK dependent proteins—have been thoroughly investigated during the last decades. Although several studies evidenced how VK may have a broader VK biological function than previously thought, including the reproduction, little is known about the specific molecular pathways. In vertebrates, sex differentiation and gametogenesis are tightly regulated processes through a highly complex molecular, cellular and tissue crosstalk. Here, VK metabolism and related pathways, as well as how gametogenesis might be impacted by VK nutritional status, will be reviewed. Critical knowledge gaps and future perspectives on how the different VK-related pathways come into play on vertebrate’s reproduction will be identified and proposed. The present review will pave the research progress to warrant a successful reproductive status through VK nutritional interventions as well as towards the establishment of reliable biomarkers for determining proper nutritional VK status in vertebrates.

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“…Vitamin K3 (showing no hydrophobic tail) has been proved to be inactive towards coagulation [27,28] and constitutes vitamins K1 and K2 catabolite product [29]. Nonetheless, the potential interactions of vitamins K1, K2, and K3 with VKORC1 remain uncharacterized, with previous studies mainly focused on vitamin K1 in its epoxide state [30,31,32]. In the present work, we aimed at describing VKORC1 activity towards different forms and states of vitamin K, to define whether the enzyme reduces preferential substrates.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown to correctly predict affinity and rank the efficiency of four VKORC1 inhibitors—warfarin, acenocoumarol, phenprocoumon, and difenacoum—using binding free energy (BFE) calculation in good correlation with experimentally measured inhibition constants. It also evidenced the C51–C132 disulfide bridge conformation as the only one able to bind vitamin K1 E [32], so we used it to perform molecular docking and molecular dynamics (MD) simulations.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

et al. 2019

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Vitamin K family molecules—phylloquinone (K1), menaquinone (K2), and menadione (K3)—act as γ-glutamyl carboxylase (GGCX)-exclusive cofactors in their hydroquinone state, activating proteins of main importance for blood coagulation in the liver and for arterial calcification prevention and energy metabolism in extrahepatic tissues. Once GGCX is activated, vitamin K is found in the epoxide state, which is then recycled to quinone and hydroquinone states by vitamin K epoxide reductase (VKORC1). Nevertheless, little information is available concerning vitamin K1, K2, or K3 tissue distribution and preferential interactions towards VKORC1. Here we present a molecular modeling study of vitamin K1, menaquinones 4, 7 (MK4, MK7), and K3 structural interactions with VKORC1. VKORC1 was shown to tightly bind vitamins K1 and MK4 in the epoxide and quinone states, but not in the hydroquinone state; five VKORC1 residues were identified as crucial for vitamin K stabilization, and two other ones were essential for hydrogen bond formation. However, vitamin MK7 revealed shaky binding towards VKORC1, induced by hydrophobic tail interactions with the membrane. Vitamin K3 exhibited the lowest affinity with VKORC1 because of the absence of a hydrophobic tail, preventing structural stabilization by the enzyme. Enzymatic activity towards vitamins K1, MK4, MK7, and K3 was also evaluated by in vitro assays, validating our in silico predictions: VKORC1 presented equivalent activities towards vitamins K1 and MK4, but much lower activity with respect to vitamin MK7, and no activity towards vitamin K3. Our results revealed VKORC1’s ability to recycle both phylloquinone and some menaquinones, and also highlighted the importance of vitamin K’s hydrophobic tail size and membrane interactions.

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Identification of the functional states of human vitamin K epoxide reductase from molecular dynamics simulations

Abstract: The functionally-related states of hVKORC1 predicted from MD conformations were assigned by probing their affinity to vitamin K and validated through analysis of its binding energy with VKAs.

Cited by 13 publications

References 74 publications

The First 3D Model of the Full-Length KIT Cytoplasmic Domain Reveals a New Look for an Old Receptor

The First 3D Model of the Full-Length KIT Cytoplasmic Domain Reveals a New Look for an Old Receptor

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

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