scholarly journals Structural Evidence: A Single Charged Residue Affects Substrate Binding in Cytochrome P450 BM-3

Biochemistry ◽  
2013 ◽  
Vol 52 (39) ◽  
pp. 6807-6815 ◽  
Author(s):  
Jaclyn Catalano ◽  
Kianoush Sadre-Bazzaz ◽  
Gabriele A. Amodeo ◽  
Liang Tong ◽  
Ann McDermott
Keyword(s):  
Cytochrome P450 ◽  
Substrate Binding ◽  
Charged Residue

Role of Cytochrome P450 in Tulip Bulb Probed by Substrate-Binding Studies

1992 ◽  
Vol 36 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Steven L. Kelly ◽  
Aysegul Topal ◽  
Ian Barnett ◽  
Diane E. Kelly ◽  
George A. F. Hendry
Keyword(s):  
Cytochrome P450 ◽  
Substrate Binding ◽  
Binding Studies ◽  
Tulip Bulb

scholarly journals Multiple substrate-binding sites are retained in cytochrome P450 3A4 mutants with decreased cooperativity

Xenobiotica ◽  
2010 ◽  
Vol 41 (4) ◽  
pp. 281-289 ◽  
Author(s):  
Harshica Fernando ◽  
Jessica A. O. Rumfeldt ◽  
Nadezhda Y. Davydova ◽  
James R. Halpert ◽  
Dmitri R. Davydov
Keyword(s):  
Cytochrome P450 ◽  
Binding Sites ◽  
Substrate Binding ◽  
Cytochrome P450 3A4 ◽  
Multiple Substrate ◽  
Substrate Binding Sites

scholarly journals Phospholipids modify substrate binding and enzyme activity of human cytochrome P450 27A1

2004 ◽  
Vol 45 (12) ◽  
pp. 2345-2353 ◽  
Author(s):  
Dilyara A. Murtazina ◽  
Ulla Andersson ◽  
In-Su Hahn ◽  
Ingemar Bjorkhem ◽  
G. A. S. Ansari ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Cytochrome P450 ◽  
Substrate Binding ◽  
Human Cytochrome

scholarly journals Point Mutations at a Key Site Alter the Cytochrome P450 OleP Structural Dynamics

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 55
Author(s):  
Linda Celeste Montemiglio ◽  
Elena Gugole ◽  
Ida Freda ◽  
Cécile Exertier ◽  
Lucia D’Auria ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Substrate Binding ◽  
Point Mutations ◽  
Conformational Space ◽  
Amino Acid Side Chain ◽  
Dynamic Simulations ◽  
Substrate Protein ◽  
Contact Points ◽  
Solvent Molecules

Substrate binding to the cytochrome P450 OleP is coupled to a large open-to-closed transition that remodels the active site, minimizing its exposure to the external solvent. When the aglycone substrate binds, a small empty cavity is formed between the I and G helices, the BC loop, and the substrate itself, where solvent molecules accumulate mediating substrate-enzyme interactions. Herein, we analyzed the role of this cavity in substrate binding to OleP by producing three mutants (E89Y, G92W, and S240Y) to decrease its volume. The crystal structures of the OleP mutants in the closed state bound to the aglycone 6DEB showed that G92W and S240Y occupied the cavity, providing additional contact points with the substrate. Conversely, mutation E89Y induces a flipped-out conformation of this amino acid side chain, that points towards the bulk, increasing the empty volume. Equilibrium titrations and molecular dynamic simulations indicate that the presence of a bulky residue within the cavity impacts the binding properties of the enzyme, perturbing the conformational space explored by the complexes. Our data highlight the relevance of this region in OleP substrate binding and suggest that it represents a key substrate-protein contact site to consider in the perspective of redirecting its activity towards alternative compounds.

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

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Liang Xu ◽  
Liao Y. Chen
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Active Site ◽  
Structural Model ◽  
Substrate Binding ◽  
Conformational Dynamics ◽  
Structural Basis ◽  
Molecular Determinant ◽  
Dynamics Simulations

AbstractCytochrome 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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