Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5

2021 ◽  
Author(s):  
Jingheng Wang ◽  
Cameron D. Buchman ◽  
Jayaraman Seetharaman ◽  
Darcie J. Miller ◽  
Andrew D. Huber ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Selective Inhibition ◽  
Structural Basis ◽  
Human Cytochrome ◽  
Cytochrome P450 3A5

A Naturally Occurring Isoform-Specific Probe for Highly Selective and Sensitive Detection of Human Cytochrome P450 3A5

2017 ◽  
Vol 60 (9) ◽  
pp. 3804-3813 ◽  
Author(s):  
Jing-Jing Wu ◽  
Yun-Feng Cao ◽  
Liang Feng ◽  
Yu-Qi He ◽  
James Y. Hong ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Sensitive Detection ◽  
Specific Probe ◽  
Naturally Occurring ◽  
Human Cytochrome ◽  
Cytochrome P450 3A5

Potent and selective inhibition of human cytochrome P450 3A4 by seco-pancratistatin structural analogs

2010 ◽  
Vol 20 (7) ◽  
pp. 2335-2339 ◽  
Author(s):  
James McNulty ◽  
Jerald J. Nair ◽  
Mohini Singh ◽  
Denis J. Crankshaw ◽  
Alison C. Holloway
Keyword(s):  
Cytochrome P450 ◽  
Selective Inhibition ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome

Effects of Histidine-Tag on Recombinant Human Cytochrome P450 3A5 Catalytic Activity in Reconstitution Systems

2009 ◽  
Vol 3 (4) ◽  
pp. 207-211 ◽  
Author(s):  
Chie Emoto ◽  
Norie Murayama ◽  
Sachiko Wakiya ◽  
Hiroshi Yamazaki
Keyword(s):  
Cytochrome P450 ◽  
Catalytic Activity ◽  
Human Cytochrome ◽  
Cytochrome P450 3A5 ◽  
Histidine Tag

scholarly journals Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5

2020 ◽  
Vol 63 (3) ◽  
pp. 1415-1433 ◽  
Author(s):  
William C. Wright ◽  
Jude Chenge ◽  
Jingheng Wang ◽  
Hazel M. Girvan ◽  
Lei Yang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Selective Inhibitor ◽  
Clobetasol Propionate ◽  
Human Cytochrome ◽  
Cytochrome P450 3A5

scholarly journals The Structural Basis for Homotropic and Heterotropic Cooperativity of Midazolam Metabolism by Human Cytochrome P450 3A4

Biochemistry ◽  
2011 ◽  
Vol 50 (50) ◽  
pp. 10804-10818 ◽  
Author(s):  
Arthur G. Roberts ◽  
Jing Yang ◽  
James R. Halpert ◽  
Sidney D. Nelson ◽  
Kenneth T. Thummel ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Basis ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Midazolam Metabolism

scholarly journals Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4

2016 ◽  
Vol 114 (3) ◽  
pp. 486-491 ◽  
Author(s):  
Irina F. Sevrioukova ◽  
Thomas L. Poulos
Keyword(s):  
Crystal Structure ◽  
Cytochrome P450 ◽  
Active Site ◽  
Structural Information ◽  
Binding Mode ◽  
Structural Basis ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Cyp3a4 Substrate

Human cytochrome P450 3A4 (CYP3A4) is a major hepatic and intestinal enzyme that oxidizes more than 60% of administered therapeutics. Knowledge of how CYP3A4 adjusts and reshapes the active site to regioselectively oxidize chemically diverse compounds is critical for better understanding structure–function relations in this important enzyme, improving the outcomes for drug metabolism predictions, and developing pharmaceuticals that have a decreased ability to undergo metabolism and cause detrimental drug–drug interactions. However, there is very limited structural information on CYP3A4–substrate interactions available to date. Despite the vast variety of drugs undergoing metabolism, only the sedative midazolam (MDZ) serves as a marker substrate for the in vivo activity assessment because it is preferentially and regioselectively oxidized by CYP3A4. We solved the 2.7 Å crystal structure of the CYP3A4–MDZ complex, where the drug is well defined and oriented suitably for hydroxylation of the C1 atom, the major site of metabolism. This binding mode requires H-bonding to Ser119 and a dramatic conformational switch in the F–G fragment, which transmits to the adjacent D, E, H, and I helices, resulting in a collapse of the active site cavity and MDZ immobilization. In addition to providing insights on the substrate-triggered active site reshaping (an induced fit), the crystal structure explains the accumulated experimental results, identifies possible effector binding sites, and suggests why MDZ is predominantly metabolized by the CYP3A enzyme subfamily.

scholarly journals Structural Basis for the Functional Roles of Critical Residues in Human Cytochrome P450 Aromatase

Biochemistry ◽  
2013 ◽  
Vol 52 (34) ◽  
pp. 5821-5829 ◽  
Author(s):  
Jessica Lo ◽  
Giovanna Di Nardo ◽  
Jennifer Griswold ◽  
Chinaza Egbuta ◽  
Wenhua Jiang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Basis ◽  
Functional Roles ◽  
P450 Aromatase ◽  
Human Cytochrome ◽  
Cytochrome P450 Aromatase ◽  
Critical Residues

scholarly journals Correction to The Structural Basis for Homotropic and Heterotropic Cooperativity of Midazolam Metabolism by Human Cytochrome P450 3A4

Biochemistry ◽  
2012 ◽  
Vol 51 (6) ◽  
pp. 1332-1332
Author(s):  
Arthur G. Roberts ◽  
Jing Yang ◽  
James R. Halpert ◽  
Sidney D. Nelson ◽  
Kenneth T. Thummel ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Basis ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Midazolam Metabolism
Sign in / Sign up

Export Citation Format

Share Document