STRUCTURE AND FUNCTION OF CYTOCHROMES-P450 - A COMPARATIVE-ANALYSIS OF 3 CRYSTAL-STRUCTURES

Background: Cytochromes P450 catalyze the oxidation of a variety of hy drophobic substrates. Sequence identities between P450 families are ge nerally low (10-30%), and consequently, the structure-function correla tions among P450s are not clear. The crystal structures of P450(terp) and the hemoprotein domain of P450(BM-3) were recently determined, and are compared here with the previously available structure of P450(cam ). Results: The topology of all three enzymes is quite similar. The he me-binding core structure is well conserved, except for local differen ces in the I helices. The greatest variation is observed in the substr ate-binding regions. The structural superposition of the proteins perm its an improved sequence alignment of other P450s. The charge distribu tion in the three structures is similarly asymmetric and defines a mol ecular dipole. Conclusions: Based on this comparison we believe that a ll P450s will be found to possess the same tertiary structure. The abi lity to precisely predict other P450 substratecontact residues is limi ted by the extreme structural heterogeneity in the substrate-recogniti on regions. The central I-helix structures of P450(terp) and P45O(BM-3 ) suggest a role for helix-associated solvent molecules as a source of catalytic protons, distinct from the mechanism for P450(cam). We sugg est that the P450 molecular dipole for P450 might aid in both redox-pa rtner docking and proton recruitment for catalysis.