4K9U

Complex of human CYP3A4 with a desoxyritonavir analog

4K9U の概要

• エントリーDOI: 10.2210/pdb4k9u/pdb
• 関連するPDBエントリー: 3NXU 4I4G 4I4H 4K9T 4K9V 4K9W 4K9X
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, N~2~-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-N-[(2S,5S)-5-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}hexan-2-yl]-D-valinamide (3 entities in total)
• 機能のキーワード: cytochrome p450 3a4, alpha-beta protein, cytochrome p450 fold, monooxygenase, cytochrome p450 reductase, endoplasmic reticulum, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Single-pass membrane protein: P08684
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57479.81

構造登録者

Sevrioukova, I.F.,Poulos, T.L. (登録日: 2013-04-21, 公開日: 2013-06-19, 最終更新日: 2023-09-20)

主引用文献

Sevrioukova, I.F.,Poulos, T.L.
Dissecting Cytochrome P450 3A4-Ligand Interactions Using Ritonavir Analogues.
Biochemistry, 52:4474-4481, 2013

PubMed Abstract: Cytochrome P450 3A4 (CYP3A4) inhibitors ritonavir and cobicistat, currently administered to HIV patients as pharmacoenhancers, were designed on the basis of the chemical structure/activity relationships rather than the CYP3A4 crystal structure. To better understand the structural basis for CYP3A4 inhibition and the ligand binding process, we investigated five desoxyritonavir analogues to elucidate how substitution/elimination of the phenyl side groups (Phe-1 and Phe-2) and removal of the isopropyl-thiazole (IPT) moiety affect affinity, inhibitory potency, and the ligand binding mode. Our experimental and structural data indicate that the side group size reduction not only drastically lowers affinity and inhibitory potency for CYP3A4 but also leads to multiple binding modes. Regardless of the side group chemical nature and the number of molecules bound, the space adjacent to the 369-371 peptide and Arg105 (Phe-2 site) is always occupied and, hence, must be a critically important binding site. When possible, the ligands also try to fill the pocket near the I-helix (Phe-1 site), even if it causes steric hindrance. Extensive hydrophobic interactions established at the Phe-1 site improve inhibitory potency, whereas contacts provided by IPT might strengthen the Fe-N bond. Overall, however, the end group contributes less to the ligand association process, which, in contrast, is greatly facilitated by the polar interactions mediated by the active site Ser119.

PubMed: 23746300
DOI: 10.1021/bi4005396

実験手法

X-RAY DIFFRACTION (2.85 Å)