Incorporation of charged residues in the CYP2J2 F-G loop disrupts CYP2J2–lipid bilayer interactions

McDougle, Daniel R.; Baylon, Javier L.; Meling, Daryl D.; Kambalyal, Amogh; Grinkova, Yelena V.; Hammernik, Jared A.; Tajkhorshid, Emad; Das, Aditi

doi:10.1016/j.bbamem.2015.07.015

Cited by 34 publications

(57 citation statements)

References 64 publications

(102 reference statements)

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“…Using molecular dynamics simulations, McDougle et al (2015) showed the proposed binding orientation of CYP2J2 to the membrane, suggesting an interaction among several hydrophobic residues in the F-G loop and the membrane. On the basis of these results, specific F-G loop mutations were generated, replacing hydrophobic Ile-236 and Phe-239 with Asp and His, respectively.…”

Section: Anionic Phospholipidsmentioning

confidence: 99%

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Brignac‐Huber¹,

Park²,

Reed³

et al. 2016

Drug Metab Dispos

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Cytochrome P450s (P450s) comprise a superfamily of proteins that catalyze numerous monooxygenase reactions in animals, plants, and bacteria. In eukaryotic organisms, these proteins not only carry out reactions necessary for the metabolism of endogenous compounds, but they are also important in the oxidation of exogenous drugs and other foreign compounds. Eukaryotic P450 system proteins generally reside in membranes, primarily the endoplasmic reticulum or the mitochondrial membrane. These membranes provide a scaffold for the P450 system proteins that facilitate interactions with their redox partners as well as other P450s. This review focuses on the ability of specific lipid components to influence P450 activities, as well as the role of the membrane in P450 function. These studies have shown that P450s and NADPH-cytochrome P450 reductase appear to selectively associate with specific phospholipids and that these lipid-protein interactions influence P450 activities. Finally, because of the heterogeneous nature of the endoplasmic reticulum as well as other biologic membranes, the phospholipids are not arranged randomly but associate to generate lipid microdomains. Together, these characteristics can affect P450 function by 1) altering the conformation of the proteins, 2) influencing the P450 interactions with their redox partners, and 3) affecting the localization of the proteins into specific membrane microdomains.

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Section: Anionic Phospholipidsmentioning

confidence: 99%

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Brignac‐Huber¹,

Park²,

Reed³

et al. 2016

Drug Metab Dispos

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“…3C). 44 This analysis showed an average interaction energy of – 86.2 ± 14.8 kcal/mol for E314, −8.0 ± 2.9 kcal/mol for F310, and −1.7 ± 2.4 kcal/mol for T219 with O-AEA. These results demonstrate that E314 plays a key role in stabilization of O-AEA, binding almost completely throughout the simulation with some transient unbinding, while being stabilized by nearby hydrophobic residues.…”

Section: Resultsmentioning

confidence: 89%

“…Nanodiscs were assembled based on previously reported methods. 11,44,64,65 Nanodiscs are used to increase solubility and stabilization of membrane proteins. 42,35,66 …”

Section: Resultsmentioning

confidence: 99%

“…46 The resulting MD simulation was used to fully sample the dynamics of CYP2J2, allowing for a myriad of snapshots to be used for the ensemble docking protocol. 44 Specifically, the last 20 ns of the simulation trajectory were used, where 200 unique protein snapshots were taken every 100 ps. To perform ensemble molecular docking, a 22.5 × 22.5 × 22.5 Å grid box was used, positioned at the center of the catalytic site of CYP2J2, containing the heme group.…”

Section: Introductionmentioning

confidence: 99%

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Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

et al. 2018

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The human body contains endogenous cannabinoids (endocannabinoids) that elicit similar effects as Δ9-tetrahydrocanabinol, the principal bioactive component of cannabis. The endocannabinoid virodhamine (O-AEA) is the constitutional isomer of the well-characterized cardioprotective and anti-inflammatory endocannabinoid anandamide (AEA). The chemical structures of O-AEA and AEA contain arachidonic acid (AA) and ethanolamine, however AA in O-AEA is connected to ethanolamine via an ester linkage whereas AA in AEA is connected through an amide linkage. We show that O-AEA is found at 9.6 fold higher levels than AEA in porcine left ventricle and is involved in regulating blood pressure and cardiovascular function. On a separate note, the cytochrome P450 (CYP) epoxygenase CYP2J2 is the most abundant CYP in the heart where it catalyzes the metabolism of AA and AA-derived eCBs to bioactive epoxides that are involved in diverse cardiovascular functions. Herein, using competitive binding studies, kinetic metabolism measurements, molecular dynamics and wound healing assays we have shown that O-AEA is an endogenous inhibitor of CYP2J2 epoxygenase. Together, the role of O-AEA as an endogenous eCB inhibitor of CYP2J2 may provide a new mode of regulation to control the activity of cardiovascular CYP2J2 in vivo and suggests a potential cross talk between the cardiovascular endocannabinoids and cytochrome P450 system.

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“…There are many examples of the application of the HMMM to real biological systems now in the literature by both our own lab [74, 77–81, 83, 84] and others [85, 86], and we have chosen a subset to review here that particularly highlight the potential impact of the HMMM to react to as well as guide experiment. Specifically, we will highlight recent work on identifying the binding face of hemagglutinin fusion peptide [81] and human cytochrome P450 [77, 84], conformational changes induced by membrane binding in talin [80] and α -Synuclein [78], as well as ongoing work in assembling blood coagulation factors on the membrane surface [74, 83]. …”

Section: Complementing Experiments With Simulation At the Membrane mentioning

confidence: 99%

Atomic-level description of protein–lipid interactions using an accelerated membrane model

Baylon

Vermaas

Müller

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Peripheral membrane proteins are structurally diverse proteins that are involved in fundamental cellular processes. Their activity of these proteins is frequently modulated through their interaction with cellular membranes, and as a result techniques to study the interfacial interaction between peripheral proteins and the membrane are in high demand. Due to the fluid nature of the membrane and the reversibility of protein–membrane interactions, the experimental study of these systems remains a challenging task. Molecular dynamics simulations offer a suitable approach to study protein–lipid interactions; however, the slow dynamics of the lipids often prevents sufficient sampling of specific membrane–protein interactions in atomistic simulations. To increase lipid dynamics while preserving the atomistic detail of protein–lipid interactions, in the highly mobile membrane-mimetic (HMMM) model the membrane core is replaced by an organic solvent, while short-tailed lipids provide a nearly complete representation of natural lipids at the organic solvent/water interface. Here, we present a brief introduction and a summary of recent applications of the HMMM to study different membrane proteins, complementing the experimental characterization of the presented systems, and we offer a perspective of future applications of the HMMM to study other classes of membrane proteins.

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Incorporation of charged residues in the CYP2J2 F-G loop disrupts CYP2J2–lipid bilayer interactions

Cited by 34 publications

References 64 publications

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

Atomic-level description of protein–lipid interactions using an accelerated membrane model

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