Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450TT

Zhanfeng Wang, Sason Shaik*, Binju Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Cytochrome P450 monooxygenases (P450s) are versatile biocatalysts used in natural products biosynthesis, xenobiotic metabolisms, and biotechnologies. In P450s, the electrons required for O 2 activation are supplied by NAD(P)H through stepwise electron transfers (ETs) mediated by redox partners. While much is known about the machinery of the catalytic cycle of P450s, the mechanisms of long-range ET are largely unknown. Very recently, the first crystal structure of full-length P450 TT was solved. This enables us to decipher the interdomain ET mechanism between the [2Fe-2S]-containing ferredoxin and the heme, by use of molecular dynamics simulations. In contrast to the "distal" conformation characterized in the crystal structure where the [2Fe-2S] cluster is ∼28 Å away from heme-Fe, our simulations demonstrated a "proximal" conformation of [2Fe-2S] that is ∼17 Å [and 13.7 Å edge-to-edge] away from heme-Fe, which may enable the interdomain ET. Key residues involved in ET pathways and interdomain complexation were identified, some of which have already been verified by recent mutation studies. The conformational transit of ferredoxin between "distal" and "proximal" was found to be controlled mostly by the long-range electrostatic interactions between the ferredoxin domain and the other two domains. Furthermore, our simulations show that the full-length P450 TT utilizes a flexible ET pathway that resembles either P450 Scc or P450 cam. Thus, this study provides a uniform picture of the ET process between reductase domains and heme domain.

Original languageEnglish
Pages (from-to)1005-1016
Number of pages12
JournalJournal of the American Chemical Society
Volume143
Issue number2
StatePublished - 20 Jan 2021

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© 2021 American Chemical Society.

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