7SV2

Human Cytochrome P450 (CYP) 3A5 ternary complex with azamulin

7SV2 の概要

• エントリーDOI: 10.2210/pdb7sv2/pdb
• 分子名称: Cytochrome P450 3A5, PROTOPORPHYRIN IX CONTAINING FE, (3aS,4R,5S,6R,8R,9R,9aR,10R)-6-ethyl-5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propanocyclopenta[8]annulen-8-yl [(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]acetate, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, binding properties, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 225745.48

構造登録者

Hsu, M.,Johnson, E.F. (登録日: 2021-11-18, 公開日: 2022-05-18, 最終更新日: 2023-10-18)

主引用文献

Hsu, M.H.,Johnson, E.F.
Structural characterization of the homotropic cooperative binding of azamulin to human cytochrome P450 3A5.
J.Biol.Chem., 298:101909-101909, 2022

PubMed Abstract: Cytochrome P450 3A4 and 3A5 catalyze the metabolic clearance of a large portion of therapeutic drugs. Azamulin is used as a selective inhibitor for 3A4 and 3A5 to define their roles in metabolism of new chemical entities during drug development. In contrast to 3A4, 3A5 exhibits homotropic cooperativity for the sequential binding of two azamulin molecules at concentrations used for inhibition. To define the underlying sites and mechanisms for cooperativity, an X-ray crystal structure of 3A5 was determined with two azamulin molecules in the active site that are stacked in an antiparallel orientation. One azamulin resides proximal to the heme in a pose similar to the 3A4-azamulin complex. Comparison to the 3A5 apo structure indicates that the distal azamulin in 3A5 ternary complex causes a significant induced fit that excludes water from the hydrophobic surfaces of binding cavity and the distal azamulin, which is augmented by the stacking interaction with the proximal azamulin. Homotropic cooperativity was not observed for the binding of related pleuromutilin antibiotics, tiamulin, retapamulin, and lefamulin, to 3A5, which are larger and unlikely to bind in the distal site in a stacked orientation. Formation of the 3A5 complex with two azamulin molecules may prevent time-dependent inhibition that is seen for 3A4 by restricting alternate product formation and/or access of reactive intermediates to vulnerable protein sites. These results also contribute to a better understanding of sites for cooperative binding and the differential structural plasticity of 3A5 and 3A4 that contribute to differential substrate and inhibitor binding.

PubMed: 35398097
DOI: 10.1016/j.jbc.2022.101909

実験手法

X-RAY DIFFRACTION (2.46 Å)