Journal Article

FZJ-2021-00767

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png All-Atom Simulations Disclose How Cytochrome Reductase Reshapes the Substrate Access/Egress Routes of Its Partner CYP450s

Ritacco, I. ; Saltalamacchia, A. ; Spinello, A. ; Ippoliti, E.FZJ* ; Magistrato, A. (Corresponding author)

2020
ACS Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/27017  doi:10.1021/acs.jpclett.9b03798

Abstract: Cytochromes P450 enzymes (CYP450s) promote the oxidative metabolism of a variety of substrates via the electrons supplied by the cytochrome P450 reductase (CPR) and upon formation of a CPR/CYP450 adduct. In spite of the pivotal regulatory importance of this process, the impact of CPR binding on the functional properties of its partner CYP450 remains elusive. By performing multiple microsecond-long all-atom molecular dynamics simulations of a 520 000-atom model of a CPR/CYP450 adduct embedded in a membrane mimic, we disclose the molecular terms for their interactions, considering the aromatase (HA) enzyme as a proxy of the CYP450 family. Our study strikingly unveils that CPR binding alters HA’s functional motions, bolstering a change in the shape and type of the channels traveled by substrates/products during their access/egress to/from the enzyme’s active site. Our outcomes unprecedentedly contribute to extricate the many entangled facets of the CYP450 metabolon, redrafting its intricate panorama from an atomic-level perspective.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. JARA - HPC (JARA-HPC)

Research Program(s):

1. 899 - ohne Topic (POF3-899) (POF3-899)
2. Post-Transcriptional regulation mechanism of Human Aromatase investigated by molecular simulations (jias5a_20190501) (jias5a_20190501)

Appears in the scientific report 2020

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Database coverage:
; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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