Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2

Lafite, Pierre; André, François; Graves, Joan P.; Zeldin, Darryl C.; Dansette, Patrick M.; Mansuy, Daniel

doi:10.3390/ijms19072066

Cited by 7 publications

(3 citation statements)

References 69 publications

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“…From our simulations, it was found that these three probes were capable of binding to the catalytic site of CYP2J2, especially for M2 and M3 even when their initial binding poses deviated from the final active conformers, indicating a high binding preference of M2 and M3 to CYP2J2. The distance from the heme iron to the metabolic site of the substrate was assumed to be related to the rate of metabolism of CYP2J2 12,31 . Based on this assumption, M1 (3.7 ± 0.2 Å) should exhibit a higher reactivity than M3 (4.3 ± 0.1 Å), which seemed to contradict the experimental results.…”

Section: Structural Basis For the High Binding Affinity Of M2 To Cyp2j2mentioning

confidence: 99%

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Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Chen

2020

Sci Rep

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Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.

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Section: Structural Basis For the High Binding Affinity Of M2 To Cyp2j2mentioning

confidence: 99%

“…For the terfenadone derivatives M10 and M12 in Fig. 1, CYP2J2 exhibited regioselectivity of hydroxylation of the Cβ atom, and Arg117 was assumed to play a critical role 12,31 . Based on the homology model of CYP2J2, a narrow channel of access to the heme was identified, which included Ile127, Phe310, Ile376, and Val380 12 .…”

Section: M1-m3mentioning

confidence: 99%

Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

Chen

2020

Sci Rep

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“…In previous work, our groups investigated the interaction of AA with human CYP2J2 and revealed Arg117 as a key player in the recognition of this substrate [3], although these simulations were relatively short (50 ns). Simulations from other studies have come to diverse conclusions about the role of individual residues in the active site [4–6]. Here, we tried to investigate further using much more extensive simulations of both wild type and mutant forms of the enzyme.…”

Section: Objectivementioning

confidence: 99%

Molecular dynamics simulations of the interaction of wild type and mutant human CYP2J2 with polyunsaturated fatty acids

2019

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ObjectivesThe data presented here is part of a study that was aimed at characterizing the molecular mechanisms of polyunsaturated fatty acid metabolism by CYP2J2, the main cytochrome P450 enzyme active in the human cardiovasculature. This part comprises the molecular dynamics simulations of the binding of three eicosanoid substrates to wild type and mutant forms of the enzyme. These simulations were carried out with the aim of dissecting the importance of individual residues in the active site and the roles they might play in dictating the binding and catalytic specificity exhibited by CYP2J2.Data descriptionThe data comprise: (a) a new homology model of CYP2J2, (b) a number of predicted low-energy complexes of CYP2J2 with arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, produced with molecular docking and (c) a series of molecular dynamics simulations of the wild type and four mutants interacting with arachidonic acid as well as simulations of the wild type interacting with the two other eicosanoid ligands. The simulations may be helpful in identifying the determinants of substrate specificity of this enzyme and in unraveling the role of individual mutations on its function. They may also help guide the generation of mutants with altered substrate preferences.

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