4y8w

Crystal Structure of Human Cytochrome P450 21A2 Progesterone Complex

spinqualitylabelsall models 4y8w, resolution 2.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4y8w is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, SO4, STR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Cytochrome P450 (P450) 21A2 is the major steroid 21-hydroxylase, and deficiency of this enzyme is involved in ~ 95% of cases of human congenital adrenal hyperplasia, a disorder of adrenal steroidogenesis. A structure of the bovine enzyme we previously published (Zhao, B. et al. (2012) J. Biol. Chem. 287, 10613-10622), containing two molecules of the substrate 17alpha-hydroxyprogesterone, has been used as a template for understanding genetic deficiencies. We have now obtained a crystal structure of human P450 21A2 in complex with progesterone, a substrate in adrenal 21-hydroxylation. Substrate binding and release were fast for human P450 21A2 with both substrates, and pre-steady-state kinetics showed a partial burst but only with progesterone as substrate and not 17alpha-hydroxyprogesterone. High intermolecular non-competitive kinetic deuterium isotope effects on both kcat and kcat/Km (5-11) were observed with both substrates, indicative of rate-limiting C-H bond cleavage and suggesting that the juxtaposition of the C21 carbon in the active site is critical for efficient oxidation. The estimated rate of binding of the substrate progesterone (kon 2.4 x 107 M-1 s-1) is only ~ 2-fold greater than the catalytic efficiency (kcat/Km 1.3 x 107 M-1 s-1) with this substrate, suggesting that the rate of substrate binding may also be partially rate-limiting. The structure of the human P450 21A2-substrate complex provides direct insight into mechanistic effects of genetic variants. Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase: Structure of the Enzyme-Progesterone Substrate Complex and Rate-Limiting C-H Bond Cleavage.,Pallan PS, Wang C, Lei L, Yoshimoto FK, Auchus RJ, Waterman MR, Guengerich FP, Egli M J Biol Chem. 2015 Apr 8. pii: jbc.M115.646307. PMID:25855791 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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