2HI4

Crystal Structure of Human Microsomal P450 1A2 in complex with alpha-naphthoflavone

Summary for 2HI4

• Entry DOI: 10.2210/pdb2hi4/pdb
• Related: 1PQ2 1R90 1TQN 1Z10
• Descriptor: Cytochrome P450 1A2, PROTOPORPHYRIN IX CONTAINING FE, 2-PHENYL-4H-BENZO[H]CHROMEN-4-ONE, ... (4 entities in total)
• Functional Keywords: cyp1a2, p450 1a2, p450, monooxygenase, drug metabolizing enzyme, alpha-naphthoflavone, benzo(h)flavone, 7, 8-benzoflavone, oxidoreductase, heme
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P05177
• Total number of polymer chains: 1
• Total formula weight: 57182.37

Authors

Sansen, S.,Yano, J.K.,Reynald, R.L.,Schoch, G.S.,Stout, C.D.,Johnson, E.F. (deposition date: 2006-06-29, release date: 2007-02-20, Last modification date: 2023-08-30)

Primary citation

Sansen, S.,Yano, J.K.,Reynald, R.L.,Schoch, G.A.,Griffin, K.J.,Stout, C.D.,Johnson, E.F.
Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2.
J.Biol.Chem., 282:14348-14355, 2007

PubMed Abstract: Microsomal cytochrome P450 family 1 enzymes play prominent roles in xenobiotic detoxication and procarcinogen activation. P450 1A2 is the principal cytochrome P450 family 1 enzyme expressed in human liver and participates extensively in drug oxidations. This enzyme is also of great importance in the bioactivation of mutagens, including the N-hydroxylation of arylamines. P450-catalyzed reactions involve a wide range of substrates, and this versatility is reflected in a structural diversity evident in the active sites of available P450 structures. Here, we present the structure of human P450 1A2 in complex with the inhibitor alpha-naphthoflavone, determined to a resolution of 1.95 A. alpha-Naphthoflavone is bound in the active site above the distal surface of the heme prosthetic group. The structure reveals a compact, closed active site cavity that is highly adapted for the positioning and oxidation of relatively large, planar substrates. This unique topology is clearly distinct from known active site architectures of P450 family 2 and 3 enzymes and demonstrates how P450 family 1 enzymes have evolved to catalyze efficiently polycyclic aromatic hydrocarbon oxidation. This report provides the first structure of a microsomal P450 from family 1 and offers a template to study further structure-function relationships of alternative substrates and other cytochrome P450 family 1 members.

PubMed: 17311915
DOI: 10.1074/jbc.M611692200

Experimental method

X-RAY DIFFRACTION (1.95 Å)