6O5Y

Structure of Human Cytochrome P450 1A1 with 5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide)

6O5Y の概要

• エントリーDOI: 10.2210/pdb6o5y/pdb
• 分子名称: Cytochrome P450 1A1, PROTOPORPHYRIN IX CONTAINING FE, 5-amino-N-{5-[(4R,5R)-4-amino-5-fluoroazepan-1-yl]-1-methyl-1H-pyrazol-4-yl}-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide, ... (5 entities in total)
• 機能のキーワード: cyp1a1, p450, oxidoreductase, gdc-0339
• 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: 226770.07

構造登録者

Bart, A.G.,Scott, E.E. (登録日: 2019-03-04, 公開日: 2019-12-04, 最終更新日: 2023-10-11)

主引用文献

Bart, A.G.,Takahashi, R.H.,Wang, X.,Scott, E.E.
Human Cytochrome P450 1A1 Adapts Active Site for Atypical Nonplanar Substrate.
Drug Metab.Dispos., 48:86-92, 2020

PubMed Abstract: The human cytochrome P450 1A1 (CYP1A1) is well known for chemical activation of procarcinogens and often has a substrate scope of small and highly planar compounds. Substrates deviating from these characteristics are certainly known, but how these larger and nonplanar substrates are accommodated and oriented within the CYP1A1 active site is not understood. Herein a new X-ray structure of CYP1A1 bound to the pan-Pim kinase inhibitor GDC-0339 reveals how the CYP1A1 active site cavity is reconfigured to bind larger and nonplanar compounds. The shape and size of the cavity are controlled by structural elements in the active site roof, with major changes in the conformation of the F helix break and relocation of Phe224 from the active site to the protein surface. This altered CYP1A1 active site architecture is consistent with the proposed mechanism for CYP1A1 generation of an unusual aminoazepane-rearranged metabolite for this substrate. SIGNIFICANCE STATEMENT: Cytochrome P450 1A1 metabolizes drugs, procarcinogens, and toxins and although previous structures have revealed how its stereotypical planar, aromatic compounds are accommodated in the CYP1A1 active site, this is not the case for flexible and nonplanar compounds. The current work determines the X-ray structure of CYP1A1 with such a flexible, nonplanar Pim kinase inhibitor, revealing significant modification of the CYP1A1 roof that accommodate this preclinical candidate and support an unusual intramolecular rearrangement reaction.

PubMed: 31757797
DOI: 10.1124/dmd.119.089607

実験手法

X-RAY DIFFRACTION (3.17 Å)