Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia.
J Biomol Struct Dyn
; 38(5): 1425-1434, 2020 Mar.
Article
em En
| MEDLINE
| ID: mdl-30982438
Congenital adrenal hyperplasia is an inherited autosomal recessive disorder related to deficient cortisol synthesis. The deficiency of steroid 21-hydroxylase (cytochrome P450 21A2), an enzyme involved in cortisol synthesis, is responsible for â¼95% of cases of congenital adrenal hyperplasia. This metabolic disease exhibits three clinical forms: salt-wasting, simple virilizing, and non-classical form, which are divided according to the degree of severity. In the present study, structural and mutational analyses were performed in order to identify the structural impact of mutations on cytochrome P450 21A2 and correlate them with patient clinical severity. The following mutations were selected: arginine-356 to tryptophan (R356W), proline-30 to leucine (P30L), isoleucine-172 to asparagine (I172N), valine-281 to leucine (V281L), and the null mutation glutamine-318 (Q318X). Our computational approach mapped the location of residues on P450 and identified their implications on enzyme electrostatic potential mapping to progesterone and heme binding pockets. Using molecular dynamics simulations, we analyzed the structural stability of ligand binding and protein structure, as well as possible conformational changes at the catalytic pocket that leads to impairment of enzymatic activity. Our study sheds light on the impact structural mutations have over steroid 21-hydroxylase structure-function in the cell.Communicated by Ramaswamy H. Sarma.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esteroide 21-Hidroxilase
/
Hiperplasia Suprarrenal Congênita
Limite:
Humans
Idioma:
En
Revista:
J Biomol Struct Dyn
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Reino Unido