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

Author(s):  
Jingheng Wang ◽  
Cameron D. Buchman ◽  
Jayaraman Seetharaman ◽  
Darcie J. Miller ◽  
Andrew D. Huber ◽  
...  
2017 ◽  
Vol 60 (9) ◽  
pp. 3804-3813 ◽  
Author(s):  
Jing-Jing Wu ◽  
Yun-Feng Cao ◽  
Liang Feng ◽  
Yu-Qi He ◽  
James Y. Hong ◽  
...  

2010 ◽  
Vol 20 (7) ◽  
pp. 2335-2339 ◽  
Author(s):  
James McNulty ◽  
Jerald J. Nair ◽  
Mohini Singh ◽  
Denis J. Crankshaw ◽  
Alison C. Holloway

2009 ◽  
Vol 3 (4) ◽  
pp. 207-211 ◽  
Author(s):  
Chie Emoto ◽  
Norie Murayama ◽  
Sachiko Wakiya ◽  
Hiroshi Yamazaki

2020 ◽  
Vol 63 (3) ◽  
pp. 1415-1433 ◽  
Author(s):  
William C. Wright ◽  
Jude Chenge ◽  
Jingheng Wang ◽  
Hazel M. Girvan ◽  
Lei Yang ◽  
...  

Biochemistry ◽  
2011 ◽  
Vol 50 (50) ◽  
pp. 10804-10818 ◽  
Author(s):  
Arthur G. Roberts ◽  
Jing Yang ◽  
James R. Halpert ◽  
Sidney D. Nelson ◽  
Kenneth T. Thummel ◽  
...  

2016 ◽  
Vol 114 (3) ◽  
pp. 486-491 ◽  
Author(s):  
Irina F. Sevrioukova ◽  
Thomas L. Poulos

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.


Biochemistry ◽  
2013 ◽  
Vol 52 (34) ◽  
pp. 5821-5829 ◽  
Author(s):  
Jessica Lo ◽  
Giovanna Di Nardo ◽  
Jennifer Griswold ◽  
Chinaza Egbuta ◽  
Wenhua Jiang ◽  
...  

Biochemistry ◽  
2012 ◽  
Vol 51 (6) ◽  
pp. 1332-1332
Author(s):  
Arthur G. Roberts ◽  
Jing Yang ◽  
James R. Halpert ◽  
Sidney D. Nelson ◽  
Kenneth T. Thummel ◽  
...  

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