Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F21%3A00554790" target="_blank" >RIV/68081707:_____/21:00554790 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15640/21:73611186 RIV/00216224:14310/21:00122232

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jpcb.1c03541" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jpcb.1c03541</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jpcb.1c03541" target="_blank" >10.1021/acs.jpcb.1c03541</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration

Popis výsledku v původním jazyce

The YTH domain of YTHDC1 belongs to a class of protein readers, recognizing the N6-methyladenosine (m(6)A) chemical modification in mRNA. Static ensemble-averaged structures revealed details of N6-methyl recognition via a conserved aromatic cage. Here, we performed molecular dynamics (MD) simulations along with nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) to examine how dynamics and solvent interactions contribute to the m(6)A recognition and negative selectivity toward an unmethylated substrate. The structured water molecules surrounding the bound RNA and the methylated substrate's ability to exclude bulk water molecules contribute to the YTH domain's preference for m(6)A. Intrusions of bulk water deep into the binding pocket disrupt binding of unmethylated adenosine. The YTHDC1's preference for the 5'-Gm(6)A-3' motif is partially facilitated by a network of water-mediated interactions between the 2amino group of the guanosine and residues in the m(6)A binding pocket. The 5'-Im(6)A-3' (where I is inosine) motif can be recognized too, but disruption of the water network lowers affinity. The D479A mutant also disrupts the water network and destabilizes m(6)A binding. Our interdisciplinary study of the YTHDC1 protein-RNA complex reveals an unusual physical mechanism by which solvent interactions contribute toward m(6)A recognition.

Název v anglickém jazyce

Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration

Popis výsledku anglicky

The YTH domain of YTHDC1 belongs to a class of protein readers, recognizing the N6-methyladenosine (m(6)A) chemical modification in mRNA. Static ensemble-averaged structures revealed details of N6-methyl recognition via a conserved aromatic cage. Here, we performed molecular dynamics (MD) simulations along with nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) to examine how dynamics and solvent interactions contribute to the m(6)A recognition and negative selectivity toward an unmethylated substrate. The structured water molecules surrounding the bound RNA and the methylated substrate's ability to exclude bulk water molecules contribute to the YTH domain's preference for m(6)A. Intrusions of bulk water deep into the binding pocket disrupt binding of unmethylated adenosine. The YTHDC1's preference for the 5'-Gm(6)A-3' motif is partially facilitated by a network of water-mediated interactions between the 2amino group of the guanosine and residues in the m(6)A binding pocket. The 5'-Im(6)A-3' (where I is inosine) motif can be recognized too, but disruption of the water network lowers affinity. The D479A mutant also disrupts the water network and destabilizes m(6)A binding. Our interdisciplinary study of the YTHDC1 protein-RNA complex reveals an unusual physical mechanism by which solvent interactions contribute toward m(6)A recognition.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10406 - Analytical chemistry

Projekt

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

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

Journal of Physical Chemistry B

ISSN

1520-6106

e-ISSN

1520-5207

Svazek periodika

125

Číslo periodika v rámci svazku

28

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

7691-7705

Kód UT WoS článku

000677581100012

EID výsledku v databázi Scopus

2-s2.0-85111217353