3T3R

Human Cytochrome P450 2A6 in complex with Pilocarpine

Summary for 3T3R

• Entry DOI: 10.2210/pdb3t3r/pdb
• Related: 1Z10 1Z11 2FDU 2FDV 2FDW 2FDY 2PG5 2PG6 2PG7 3EBS 3T3Q 3T3S 3T3Z
• Descriptor: Cytochrome P450 2A6, PROTOPORPHYRIN IX CONTAINING FE, (3S,4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]dihydrofuran-2(3H)-one, ... (4 entities in total)
• Functional Keywords: cyp2a6, cytochrome p450 2a6, p450 2a6, heme protein, monooxygenase, drug metabolism, xenobiotic metabolism, endoplasmic reticulum, membrane, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P11509
• Total number of polymer chains: 4
• Total formula weight: 221985.52

Authors

DeVore, N.M.,Scott, E.E. (deposition date: 2011-07-25, release date: 2011-12-07, Last modification date: 2023-09-13)

Primary citation

DeVore, N.M.,Meneely, K.M.,Bart, A.G.,Stephens, E.S.,Battaile, K.P.,Scott, E.E.
Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.
Febs J., 279:1621-1631, 2012

PubMed Abstract: Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 Å), CYP2A13 (3.0 Å), CYP2E1 (2.35 Å), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 Å) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine.

PubMed: 22051186
DOI: 10.1111/j.1742-4658.2011.08412.x

Experimental method

X-RAY DIFFRACTION (2.4 Å)