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Received for publication August 30, 2004.
Revised October 6, 2004.
Accepted for publication October 7, 2004.
Summary of Brodie Award Lecture Recent advances in understanding structure function relationships in P450, nitric oxide synthase (NOS), and heme oxygenase are summarized. Of particular importance is the role that dynamics plays in P450 function where the active site undergoes large open/close motions in order to enable substrates to bind and products to leave. In sharp contrast, the heme-containing active site of NOS is rigid and remains relatively exposed compared to P450s. This difference in dynamics and active site exposure requires that the O2 activation machinery operate somewhat differently in P450 and NOS. Owing to the open NOS active site, the NOS-oxy complex could be subject to non-specific protonation that short circuits the normal reaction path. One working hypothesis holds that NOS recruited the cofactor, tetrahydrobiopterin, to bind near the heme for very rapid coupled electron/proton transfer to the oxy-complex which avoids indiscriminate reaction with bulk solvent. Despite these differences, P450, NOS, and also heme oxygenase use a very similar network of H-bonded water molecules in the active site which are required for oxygen activation. Both P450 and NOS are important drug targets. With NOS, the structural basis for isoform-selective inhibition by a class of dipeptide inhibitors has been worked out thus providing the basis for structure-based drug design.
Key words:
cytochrome P450, drug design, heme oxygenases, nitric oxide synthase, P450 mechanism, structure-activity relationships
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