2PG5

Crystal Structure of Human Microsomal P450 2A6 N297Q

Summary for 2PG5

• Entry DOI: 10.2210/pdb2pg5/pdb
• Related: 1Z10 1Z11 2FDU 2FDV 2FDW 2FDY 2PG6 2PG7
• Descriptor: Cytochrome P450 2A6, PROTOPORPHYRIN IX CONTAINING FE, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: cyp2a6, p450 2a6, p450, monooxygenases, drug metabolizing enzyme, heme, mutant, indole, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P11509
• Total number of polymer chains: 4
• Total formula weight: 221456.88

Authors

Sansen, S.,Hsu, M.H.,Stout, C.D.,Johnson, E.F. (deposition date: 2007-04-06, release date: 2007-07-24, Last modification date: 2023-08-30)

Primary citation

Sansen, S.,Hsu, M.H.,Stout, C.D.,Johnson, E.F.
Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants.
Arch.Biochem.Biophys., 464:197-206, 2007

PubMed Abstract: Human P450 2A6 displays a small active site that is well adapted for the oxidation of small planar substrates. Mutagenesis of CYP2A6 resulted in an increased catalytic efficiency for indole biotransformation to pigments and conferred a capacity to oxidize substituted indoles (Wu, Z.-L., Podust, L.M., Guengerich, F.P. J. Biol. Chem. 49 (2005) 41090-41100.). Here, we describe the structural basis that underlies the altered metabolic profile of three mutant enzymes, P450 2A6 N297Q, L240C/N297Q and N297Q/I300V. The Asn297 substitution abolishes a potential hydrogen bonding interaction with substrates in the active site, and replaces a structural water molecule between the helix B'-C region and helix I while maintaining structural hydrogen bonding interactions. The structures of the P450 2A6 N297Q/L240C and N297Q/I300V mutants provide clues as to how the protein can adapt to fit the larger substituted indoles in the active site, and enable a comparison with other P450 family 2 enzymes for which the residue at the equivalent position was seen to function in isozyme specificity, structural integrity and protein flexibility.

PubMed: 17540336
DOI: 10.1016/j.abb.2007.04.028

Experimental method

X-RAY DIFFRACTION (1.95 Å)