Structure of Mammalian Cytochrome P450 2C5 Complexed with Diclofenac at 2.1 Å Resolution:  Evidence for an Induced Fit Model of Substrate Binding†,‡

Biochemistry ◽  
2003 ◽  
Vol 42 (31) ◽  
pp. 9335-9345 ◽  
Author(s):  
Michael R. Wester ◽  
Eric F. Johnson ◽  
Cristina Marques-Soares ◽  
Sylvie Dijols ◽  
Patrick M. Dansette ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Substrate Binding ◽  
Induced Fit

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 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

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.

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