Binding of Quinidine Radically Increases the Stability and Decreases the Flexibility of the Cytochrome P450 2D6 Active Site

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F12%3A33141136" target="_blank" >RIV/61989592:15310/12:33141136 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15110/12:33141136

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0162013412000542" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0162013412000542</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jinorgbio.2012.02.010" target="_blank" >10.1016/j.jinorgbio.2012.02.010</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Binding of Quinidine Radically Increases the Stability and Decreases the Flexibility of the Cytochrome P450 2D6 Active Site

Popis výsledku v původním jazyce

Human cytochrome P450 2D6 (CYP2D6) is an enzyme of the CYP superfamily responsible for biotransformation of about 20% of drugs of known metabolism containing a basic nitrogen and a planar aromatic ring. Here, we present a combined experimental and computational study on the compressibility and ?exibility of unliganded and quinidine-bound CYP2D6. Experimentally, high-pressure induced Soret band shifts of the enzyme were measured by UV/VIS spectroscopy, while 100 ns all atomic molecular dynamics (MD) simulations in explicit water were used in the computational analysis. We identi?ed sharp differences between ligand-free and quinidine-bound CYP2D6 forms in compressibility, ?exibility parameters and active site solvation. While the unliganded CYP2D6 is compressible, quinidine binding signi?cantly rigidi?es the CYP2D6 active site. In addition, MD simulations show that quinidine binding results in pronounced reductions in active site ?exibility and solvation.

Název v anglickém jazyce

Binding of Quinidine Radically Increases the Stability and Decreases the Flexibility of the Cytochrome P450 2D6 Active Site

Popis výsledku anglicky

Human cytochrome P450 2D6 (CYP2D6) is an enzyme of the CYP superfamily responsible for biotransformation of about 20% of drugs of known metabolism containing a basic nitrogen and a planar aromatic ring. Here, we present a combined experimental and computational study on the compressibility and ?exibility of unliganded and quinidine-bound CYP2D6. Experimentally, high-pressure induced Soret band shifts of the enzyme were measured by UV/VIS spectroscopy, while 100 ns all atomic molecular dynamics (MD) simulations in explicit water were used in the computational analysis. We identi?ed sharp differences between ligand-free and quinidine-bound CYP2D6 forms in compressibility, ?exibility parameters and active site solvation. While the unliganded CYP2D6 is compressible, quinidine binding signi?cantly rigidi?es the CYP2D6 active site. In addition, MD simulations show that quinidine binding results in pronounced reductions in active site ?exibility and solvation.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FR - Farmakologie a lékárnická chemie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2012

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Inorganic Biochemistry

ISSN

0162-0134

e-ISSN

—

Svazek periodika

110

Číslo periodika v rámci svazku

MAY

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

5

Strana od-do

46-50

Kód UT WoS článku

000304335700008

EID výsledku v databázi Scopus

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