Solvation of the active site of cytochrome P450-cam.
Energetically favorable water binding sites in the substrate pocket of cytochrome P450-cam have been predicted by a molecular mechanics method. Binding sites corresponding to all the experimentally observed water sites in this region of the enzyme were located. The calculations also indicate the presence of two further water binding sites. One of these is located in a hydrophobic region of the protein where a water molecule would not bind tightly to the substrate-free enzyme. However, in the substrate-bound enzyme, a water molecule in this region could donate a hydrogen bond of optimum geometry to the carbonyl oxygen atom of the camphor substrate and could therefore contribute to the correct positioning of the camphor substrate for 5-exo-hydroxylation. These calculations also suggest that a steric analogue of camphor, containing an alkyl group which could prevent a water molecule from binding in this region, might inhibit cytochrome P450-cam by forming a more stable enzyme-ligand complex than camphor itself.
Wade
R C
RC
Laboratory of Molecular Biophysics, University of Oxford, U.K.
D001665:Binding Sites; D002164:Camphor / Q000378:metabolism; D019475:Camphor 5-Monooxygenase; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003196:Computer Graphics; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015195:Drug Design; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D014867:Water / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D014867:Water; D002164:Camphor; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019475:Camphor 5-Monooxygenase