4K9V

Complex of CYP3A4 with a desoxyritonavir analog

Summary for 4K9V

• Entry DOI: 10.2210/pdb4k9v/pdb
• Related: 3NXU 4I4G 4I4H 4K9T 4K9U 4K9W 4K9X
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, 1,3-thiazol-5-ylmethyl [(3S,6S)-6-{[N-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-L-seryl]amino}octan-3-yl]carbamate, ... (4 entities in total)
• Functional Keywords: cytochrome p450 3a4, alpha-beta protein, cytochrome p450 fold, monooxygenase, cytochrome p450 reductase, endoplasmic reticulum, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Single-pass membrane protein: P08684
• Total number of polymer chains: 1
• Total formula weight: 56943.05

Authors

Sevrioukova, I.F.,Poulos, T.L. (deposition date: 2013-04-21, release date: 2013-06-19, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)