3na0
Crystal structure of human CYP11A1 in complex with 20,22-dihydroxycholesterol
Structural highlights
DiseaseCP11A_HUMAN Inherited isolated adrenal insufficiency due to CYP11A1 deficiency;46,XY disorder of sex development - adrenal insufficiency due to CYP11A1 deficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionCP11A_HUMAN Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedIn humans, the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1). This complex not only plays a key role in steroidogenesis, but also has long been a model to study electron transfer, multistep catalysis, and C-C bond cleavage performed by monooxygenases. Detailed mechanistic understanding of these processes has been hindered by a lack of structural information. Here we present the crystal structure of the complex of human Adx and CYP11A1-the first of a complex between a eukaryotic CYP and its redox partner. The structures with substrate and a series of reaction intermediates allow us to define the mechanism underlying sequential hydroxylations of the cholesterol and suggest the mechanism of C-C bond cleavage. In the complex the [2Fe-2S] cluster of Adx is positioned 17.4 A away from the heme iron of CYP11A1. This structure suggests that after an initial protein-protein association driven by electrostatic forces, the complex adopts an optimized geometry between the redox centers. Conservation of the interaction interface suggests that this mechanism is common for all mitochondrial P450s. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.,Strushkevich N, Mackenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW Proc Natl Acad Sci U S A. 2011 Jun 2. PMID:21636783[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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