title: Research Resource: Correlating Human Cytochrome P450 21A2 Crystal Structure and Phenotypes of Mutations in Congenital Adrenal Hyperplasia.
abstract: Cytochrome P450 21A2 is a key player in steroid 21-hydroxylation and converts progesterone to 11-deoxycorticosterone and 17α-hydroxy progesterone to 11-deoxycortisol. More than 100 mutations in P450 21A2 have been established in patients thus far; these account for the vast majority of occurrences of congenital adrenal hyperplasia (CAH), which is among the most common heritable metabolic diseases in humans. CAH phenotypes range from the most severe, salt-wasting (SW), to the simple virilizing (SV), and nonclassical (NC) CAH forms. We recently determined the crystal structure of human P450 21A2 in complex with progesterone. To gain more insight into the structural and stability changes underlying the phenotypes of individual mutations, we analyzed 24 SW, SV, and NC mutants in the context of the crystal structure of the human enzyme. Our analysis reveals clear differences in the localization of SW, SV, and NC mutations, with many of the first type mapping to the active site and near the heme and/or substrate and mostly resulting in complete loss of enzyme activity. Conversely, NC mutations are often found near the periphery and close to the surface of the protein, and mutant enzymes retain partial activity. The main conclusion from the mutation-structure-activity study is that the severity of the CAH clinical manifestations can be directly correlated with the degree of mutation-induced damage in terms of protein fold stability and active site changes in the structural model. Thus, the NC phenotype is typically associated with mutations that have a compensatory effect, ie, H-bonding replacing hydrophobic interactions and vice versa.
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Pallan
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: Li
authors.initials: L
authors.lastname: Lei
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: Chunxue
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.affiliation: Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: Martin
authors.initials: M
authors.lastname: Egli
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D018360:Crystallography, X-Ray; D006801:Humans; D009154:Mutation / Q000235:genetics; D011374:Progesterone / Q000378:metabolism; D017510:Protein Folding; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011374:Progesterone; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase