6H1S

Structure of the BM3 heme domain in complex with fluconazole

Summary for 6H1S

• Entry DOI: 10.2210/pdb6h1s/pdb
• Descriptor: Bifunctional cytochrome P450/NADPH--P450 reductase, 2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: p450, azole inhibitor, heme ligation, p450 bm3, oxidoreductase
• Biological source: Bacillus megaterium
• Total number of polymer chains: 2
• Total formula weight: 107502.22

Authors

Jeffreys, L.N.,Munro, A.W.M.,Leys, D. (deposition date: 2018-07-12, release date: 2019-02-20, Last modification date: 2024-01-17)

Primary citation

Jeffreys, L.N.,Poddar, H.,Golovanova, M.,Levy, C.W.,Girvan, H.M.,McLean, K.J.,Voice, M.W.,Leys, D.,Munro, A.W.
Novel insights into P450 BM3 interactions with FDA-approved antifungal azole drugs.
Sci Rep, 9:1577-1577, 2019

PubMed Abstract: Flavocytochrome P450 BM3 is a natural fusion protein constructed of cytochrome P450 and NADPH-cytochrome P450 reductase domains. P450 BM3 binds and oxidizes several mid- to long-chain fatty acids, typically hydroxylating these lipids at the ω-1, ω-2 and ω-3 positions. However, protein engineering has led to variants of this enzyme that are able to bind and oxidize diverse compounds, including steroids, terpenes and various human drugs. The wild-type P450 BM3 enzyme binds inefficiently to many azole antifungal drugs. However, we show that the BM3 A82F/F87V double mutant (DM) variant binds substantially tighter to numerous azole drugs than does the wild-type BM3, and that their binding occurs with more extensive heme spectral shifts indicative of complete binding of several azoles to the BM3 DM heme iron. We report here the first crystal structures of P450 BM3 bound to azole antifungal drugs - with the BM3 DM heme domain bound to the imidazole drugs clotrimazole and tioconazole, and to the triazole drugs fluconazole and voriconazole. This is the first report of any protein structure bound to the azole drug tioconazole, as well as the first example of voriconazole heme iron ligation through a pyrimidine nitrogen from its 5-fluoropyrimidine ring.

PubMed: 30733479
DOI: 10.1038/s41598-018-37330-y

Experimental method

X-RAY DIFFRACTION (1.95 Å)