Probing the open state of cytochrome P450cam with ruthenium-linker substrates

Cytochromes P450 play key roles in drug metabolism and disease by oxidizing a wide variety of natural and xenobiotic compounds. High-resolution crysta l structures of P450cam bound to ruthenium sensitizer-linked substrates rev eal an open conformation of the enzyme that allows substrates to access the active center via a 22-Angstrom deep channel. Interactions of alkyl and fl uorinated biphenyl linkers with the channel demonstrate the importance of e xploiting protein dynamics for specific inhibitor design. Large changes in peripheral enzyme structure (F and G helices) couple to conformational chan ges in active center residues (I helix) implicated in proton pumping and di oxygen activation. Common conformational states among P450cam and homologou s enzymes indicate that static and dynamic variability in the F/G helix reg ion allows the 54 human P450s to oxidize thousands of substrates.