8EOH
crystal structure of human Cytochrome P450 8B1 in complex with a C12-Pyridine Containing Steroid
Summary for 8EOH
| Entry DOI | 10.2210/pdb8eoh/pdb |
| Descriptor | 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, 12-(pyridin-3-yl)-8alpha,10alpha,13alpha,14beta-androsta-4,11-diene-3,17-dione, ... (4 entities in total) |
| Functional Keywords | monooxygenase, sterol 12-hydroxylase, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 58107.70 |
| Authors | Liu, J.,Scott, E.E. (deposition date: 2022-10-03, release date: 2023-08-02, Last modification date: 2024-05-22) |
| Primary citation | Liu, J.,Offei, S.D.,Yoshimoto, F.K.,Scott, E.E. Pyridine-containing substrate analogs are restricted from accessing the human cytochrome P450 8B1 active site by tryptophan 281. J.Biol.Chem., 299:103032-103032, 2023 Cited by PubMed Abstract: The human oxysterol 12α-hydroxylase cytochrome P450 8B1 (CYP8B1) is a validated drug target for both type 2 diabetes and nonalcoholic fatty liver disease, but effective selective inhibitors are not yet available. Herein, steroidal substrate-mimicking compounds with a pyridine ring appended to the C12 site of metabolism were designed as inhibitors, synthesized, and evaluated in terms of their functional and structural interactions with CYP8B1. While the pyridine nitrogen was intended to coordinate the CYP8B1 active site heme iron, none of these compounds elicited shifts in the CYP8B1 Soret absorbance consistent with this type of interaction. However, when CYP8B1 was cocrystallized with the pyridine-containing compound with the 3-keto-Δ4 steroid backbone most similar to the endogenous substrate, it was apparent that this ligand was bound in a channel leading to the active site, instead of near the heme iron. Inspection of this structure suggested that tryptophan 281 directly above the heme might restrict active site binding of potential inhibitors with this design. This hypothesis was supported when a CYP8B1 W281F mutation did allow all three compounds to coordinate the heme iron as designed. These results indicated that the design of next-generation CYP8B1 inhibitors should be compatible with the low-ceiling tryptophan immediately above the heme iron. PubMed: 36806682DOI: 10.1016/j.jbc.2023.103032 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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