title: Structure conservation in cytochromes P450.
abstract: The recent availability of crystal structures for several diverse cytochromes P450 (CYPs) offers the possibility to perform an up-to-date comparative analysis to identify the degree of structure conservation among this superfamily of enzymes specially relevant for their involvement in drug metabolism and toxicity. A set of 9 CYPs sharing between 10% and 27% sequence identity was selected, including 7 class I (CYP 101, 107, 108, 119, 121, 51, and 55) and two class II (CYP 102, and 2C5) structures. After obtaining a multiprotein structure superimposition, a structure-based sequence alignment was derived. Mapping the level of three-dimensional structural conservation onto the sequence alignment revealed that over 28% of the alignment positions have the Calpha carbons of their residues within a root-mean-square deviation (RMSD) of 2 A. This degree of structure conservation is found to be generally preserved, even when the structure undergoes dramatic conformational changes. Performing the analysis on 4 members of the CYP2 family (CYP 2B4, 2C5, 2C8, and 2C9), the percentage of alignment positions within 2 A RMSD amounted to 73%, increasing to over 85% when only structures in a closed conformation are considered. The present findings suggest that it should be plausible to derive models of overall good quality for the major CYP2 metabolizing forms (CYP 2A6, 2C19, 2D6, and 2E1), whereas high levels of uncertainty are still likely to be expected in models for the remaining 2 major P450 metabolizing forms (CYP 1A2 and 3A4), with the corresponding implications for their potential applicability in drug design activities.
authors.affiliation: Chemogenomics Laboratory, Research Unit on Biomedical Informatics, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain. jmestres@imim.es <jmestres@imim.es>
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry; D001419:Bacteria / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D000072467:Cytochrome P450 Family 2; D030562:Databases, Protein; D015195:Drug Design; D005658:Fungi / Q000378:metabolism; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016011:Normal Distribution; D011487:Protein Conformation; D040901:Proteomics / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D012984:Software; D013255:Steroid 21-Hydroxylase / Q000737:chemistry; D013250:Steroid Hydroxylases / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C065407:CYP2C5 protein, Oryctolagus cuniculus; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit); D013255:Steroid 21-Hydroxylase