This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Robins, T. Articles by Persson, B. Search for Related Content PubMed PubMed Citation Articles by Robins, T. Articles by Persson, B.

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

Department of Molecular Medicine and Surgery (T.R., A.W.), Center for Molecular Medicine, L8:02, Karolinska Institutet/Karolinska University Hospital, S-171 76 Stockholm, Sweden; The Department of Physics, Chemistry and Biology (IFM Bioinformatics) (J.C., B.P.) and Molecular Biotechnology (M.S.), Linköping University, S-581 83 Linköping, Sweden; Department of Cell and Molecular Biology (B.P.), Programme for Genomics and Bioinformatics, Karolinska Institutet, S-171 77 Stockholm, Sweden

Address all correspondence and requests for reprints to: Tiina Robins, Department of Molecular Medicine and Surgery, Center for Molecular Medicine (CMM) L8:02, Karolinska Institutet/Karolinska University Hospital, S-171 76 Stockholm, Sweden. E-mail: tiina.robins{at}ki.se.

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

This article has been cited by other articles:

				S. Parajes, L. Loidi, N. Reisch, V. Dhir, I. T. Rose, R. Hampel, M. Quinkler, G. S. Conway, L. Castro-Feijoo, D. Araujo-Vilar, et al. Functional Consequences of Seven Novel Mutations in the CYP11B1 Gene: Four Mutations Associated with Nonclassic and Three Mutations Causing Classic 11{beta}-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., February 1, 2010; 95(2): 779 - 788. [Abstract] [Full Text] [PDF]

				F. G. Riepe, O. Hiort, J. Grotzinger, W. G. Sippell, N. Krone, and P.-M. Holterhus Functional and Structural Consequences of a Novel Point Mutation in the CYP21A2 Gene Causing Congenital Adrenal Hyperplasia: Potential Relevance of Helix C for P450 Oxidoreductase-21-Hydroxylase Interaction J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2891 - 2895. [Abstract] [Full Text] [PDF]

				F. C. Soardi, M. Barbaro, I. F. Lau, S. H. V. Lemos-Marini, M. T. M. Baptista, G. Guerra-Junior, A. Wedell, S. Lajic, and M. P. de Mello Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2416 - 2420. [Abstract] [Full Text] [PDF]

				R. Menassa, V. Tardy, F. Despert, C. Bouvattier-Morel, J. P. Brossier, M. Cartigny, and Y. Morel p.H62L, a Rare Mutation of the CYP21 Gene Identified in Two Forms of 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1901 - 1908. [Abstract] [Full Text] [PDF]