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From Proteopedia
Crystal Structure of Cytochrome P450 CYP11A1 in complex with 22-hydroxy-cholesterol
Structural highlights
FunctionCP11A_BOVIN Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone. Publication Abstract from PubMedMitochondrial cytochrome P450 11A1 (CYP11A1 or P450 11A1) is the only known enzyme that cleaves the side chain of cholesterol yielding pregnenolone, the precursor of all steroid hormones. Pregnenolone is formed via three sequential monooxygenation reactions that involve the progressive production of 22R-hydroxycholesterol (22HC) and 20alpha,22R-dihydroxycholesterol followed by the cleavage of the C20-C22 bond. Herein we present the 2.5 A-crystal structure of CYP11A1 in complex with the first reaction intermediate, 22HC. The active site cavity in CYP11A1 represents a long, curved tube which extends from the protein surface to the heme group, the site of catalysis. 22HC occupies 2/3 of the cavity with the 22R-hydroxyl group nearest the heme and 2.5 A from the iron. The space at the entrance to the active site is not taken up by 22HC but filled with ordered water molecules. The network formed by these water molecules allows the soft recognition of the 22HC 3beta-hydroxyl. Such a mode of 22HC binding suggests shuttling of the sterol intermediates between the active site entrance and the heme group during the three step reaction. Translational freedom of 22HC, and torsional motion of its aliphatic tail, is supported by solution studies. The CYP11A1-22HC co-complex also provides insight into the structural basis of the enyzme's strict substrate specificity and high catalytic efficiency, and highlights conserved structural motifs involved in redox partner interactions by mitochondrial P450s. Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1.,Mast N, Annalora AJ, Lodowski DT, Palczewski K, Stout CD, Pikuleva IA J Biol Chem. 2010 Dec 15. PMID:21159775[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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