title: Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants.
abstract: Steroid 21-hydroxylase (cytochrome P450 21A2, CYP21A2) deficiency accounts for ∼95% of individuals with congenital adrenal hyperplasia, a common autosomal recessive metabolic disorder of adrenal steroidogenesis. The effects of amino acid mutations on CYP21A2 activity lead to impairment of the synthesis of cortisol and aldosterone and the excessive production of androgens. In order to understand the structural and molecular basis of this group of diseases, the bovine CYP21A2 crystal structure complexed with the substrate 17-hydroxyprogesterone (17OHP) was determined to 3.0 Å resolution. An intriguing result from this structure is that there are two molecules of 17OHP bound to the enzyme, the distal one being located at the entrance of the substrate access channel and the proximal one bound in the active site. The substrate binding features locate the key substrate recognition residues not only around the heme but also along the substrate access channel. In addition, orientation of the skeleton of the proximal molecule is toward the interior of the enzyme away from the substrate access channel. The 17OHP complex of CYP21A2 provides a good relationship between the crystal structure, clinical data, and genetic mutants documented in the literature, thereby enhancing our understanding of congenital adrenal hyperplasia. In addition, the location of certain CYP21A2 mutations provides general understanding of structure/function relationships in P450s.
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and. Electronic address: bin.zhao@vanderbilt.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and.
authors.forename: Li
authors.initials: L
authors.lastname: Lei
authors.affiliation: Global Centers of Excellence Program, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Kagawa
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and.
authors.forename: Munirathinam
authors.initials: M
authors.lastname: Sundaramoorthy
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and.
authors.forename: Surajit
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and.
authors.forename: Leslie D
authors.initials: LD
authors.lastname: Nagy
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and.
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and. Electronic address: Michael.Waterman@vanderbilt.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000737:chemistry* / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D006801:Humans; D009154:Mutation; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019326:17-alpha-Hydroxyprogesterone; D013255:Steroid 21-Hydroxylase