Molecular Model of Human CYP21 Based onMammalian CYP2C5: Structural Features Correlatewith Clinical Severity of Mutations CausingCongenital Adrenal Hyperplasia
2006 (English)In: Molecular Endocrinology, ISSN 0888-8809, Vol. 20, no 11, 2946-2964 p.Article in journal (Refereed) Published
Enhanced understanding of structure-function relationshipsof human 21-hydroxylase, CYP21, is requiredto better understand the molecular causesof congenital adrenal hyperplasia. To this end, astructural model of human CYP21 was calculatedbased on the crystal structure of rabbit CYP2C5.All but two known allelic variants of missense type,a total of 60 disease-causing mutations and sixnormal variants, were analyzed using this model. Astructural explanation for the corresponding phenotypewas found for all but two mutants for whichavailable clinical data are also discrepant with invitro enzyme activity. Calculations of protein stabilityof modeled mutants were found to correlateinversely with the corresponding clinical severity.Putative structurally important residues were identifiedto be involved in heme and substrate binding,redox partner interaction, and enzyme catalysisusing docking calculations and analysis of structurallydetermined homologous cytochrome P450s(CYPs). Functional and structural consequences ofseven novel mutations, V139E, C147R, R233G,T295N, L308F, R366C, and M473I, detected inScandinavian patients with suspected congenitaladrenal hyperplasia of different severity, were predictedusing molecular modeling. Structural featuresdeduced from the models are in good correlationwith clinical severity of CYP21 mutants,which shows the applicability of a modeling approachin assessment of new CYP21 mutations.
Place, publisher, year, edition, pages
Stanford: The endocrin society , 2006. Vol. 20, no 11, 2946-2964 p.
Mutations, prediction, CAH, CYP21, homology model
Bioinformatics and Systems Biology
IdentifiersURN: urn:nbn:se:liu:diva-21305DOI: 10.1210/me.2006-0172OAI: oai:DiVA.org:liu-21305DiVA: diva2:241009