| KREPL, Miroslav, Fred Franz DAMBERGER, Christine VON SCHROETTER, Dominik THELER, Pavlína POKORNÁ, Šponer H.-T. ALLAIN a Jiří ŠPONER. Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration. Journal of Physical Chemistry B. American Chemical Society, 2021, roč. 125, č. 28, s. 7691-7705. ISSN 1520-6106. Dostupné z: https://dx.doi.org/10.1021/acs.jpcb.1c03541. |
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@article{1789444,
author = {Krepl, Miroslav and Damberger, Fred Franz and von Schroetter, Christine and Theler, Dominik and Pokorná, Pavlína and Allain, Šponer H.andT. and Šponer, Jiří},
article_number = {28},
doi = {http://dx.doi.org/10.1021/acs.jpcb.1c03541},
keywords = {Genetics; Monomers; Molecules; Protein structure; Chemical calculations},
language = {eng},
issn = {1520-6106},
journal = {Journal of Physical Chemistry B},
title = {Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration},
url = {https://doi.org/10.1021/acs.jpcb.1c03541},
volume = {125},
year = {2021}
}
TY - JOUR
ID - 1789444
AU - Krepl, Miroslav - Damberger, Fred Franz - von Schroetter, Christine - Theler, Dominik - Pokorná, Pavlína - Allain, Šponer H.-T. - Šponer, Jiří
PY - 2021
TI - Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration
JF - Journal of Physical Chemistry B
VL - 125
IS - 28
SP - 7691-7705
EP - 7691-7705
PB - American Chemical Society
SN - 15206106
KW - Genetics
KW - Monomers
KW - Molecules
KW - Protein structure
KW - Chemical calculations
UR - https://doi.org/10.1021/acs.jpcb.1c03541
N2 - 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.
ER -
KREPL, Miroslav, Fred Franz DAMBERGER, Christine VON SCHROETTER, Dominik THELER, Pavlína POKORNÁ, Šponer H.-T. ALLAIN a Jiří ŠPONER. Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration. \textit{Journal of Physical Chemistry B}. American Chemical Society, 2021, roč.~125, č.~28, s.~7691-7705. ISSN~1520-6106. Dostupné z: https://dx.doi.org/10.1021/acs.jpcb.1c03541.
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