Molecular Model of Human CYP21 Based on Mammalian CYP2C5: Structural Features Correlate with Clinical Severity of Mutations Causing Congenital Adrenal Hyperplasia

• DOI: 10.1210/me.2006-0172
• Publication Date: 2006-06-21T04:13:27Z
• Authors: Tiina Robins; Jonas Carlsson; Maria Sunnerhagen; Anna Wedell; Bengt Persson
• Keywords: Models, Molecular; 0303 health sciences; Binding Sites; Adrenal Hyperplasia, Congenital; Molecular Sequence Data; Genetic Variation; Heme; Protein Structure, Secondary; 03 medical and health sciences; Cytochrome P-450 Enzyme System; Enzyme Stability; Mutation; Protein Interaction Mapping; Animals; Humans; Mutant Proteins; Amino Acid Sequence; Rabbits; Cytochrome P450 Family 2; Hydrophobic and Hydrophilic Interactions; Oxidation-Reduction; Protein Binding

Enhanced understanding of structure-function relationships human 21-hydroxylase, CYP21, is required to better understand the molecular causes congenital adrenal hyperplasia. To this end, a structural model CYP21 was calculated based on crystal structure rabbit CYP2C5. All but two known allelic variants missense type, total 60 disease-causing mutations and six normal variants, were analyzed using model. A explanation for corresponding phenotype found all mutants which available clinical data are also discrepant with in vitro enzyme activity. Calculations protein stability modeled correlate inversely severity. Putative structurally important residues identified be involved heme substrate binding, redox partner interaction, catalysis docking calculations analysis determined homologous cytochrome P450s (CYPs). Functional consequences seven novel mutations, V139E, C147R, R233G, T295N, L308F, R366C, M473I, detected Scandinavian patients suspected hyperplasia different severity, predicted modeling. Structural features deduced from models good correlation severity mutants, shows applicability modeling approach assessment new mutations.