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6ZD8

Crystal structure of YTHDC1 T379V mutant

6ZD8 の概要
エントリーDOI10.2210/pdb6zd8/pdb
分子名称YTHDC1, SULFATE ION (3 entities in total)
機能のキーワードythdc1, m6a, complex, inhibitor, rna binding protein
由来する生物種Homo sapiens (Human)
タンパク質・核酸の鎖数2
化学式量合計42794.94
構造登録者
Bedi, R.K.,Li, Y.,Caflisch, A. (登録日: 2020-06-14, 公開日: 2021-01-13, 最終更新日: 2024-01-24)
主引用文献Li, Y.,Bedi, R.K.,Wiedmer, L.,Sun, X.,Huang, D.,Caflisch, A.
Atomistic and Thermodynamic Analysis of N6-Methyladenosine (m 6 A) Recognition by the Reader Domain of YTHDC1.
J Chem Theory Comput, 17:1240-1249, 2021
Cited by
PubMed Abstract: N6-Methyladenosine (mA) is the most frequent modification in eukaryotic messenger RNA (mRNA) and its cellular processing and functions are regulated by the reader proteins YTHDCs and YTHDFs. However, the mechanism of mA recognition by the reader proteins is still elusive. Here, we investigate this recognition process by combining atomistic simulations, site-directed mutagenesis, and biophysical experiments using YTHDC1 as a model. We find that the N6 methyl group of mA contributes to the binding through its specific interactions with an aromatic cage (formed by Trp377 and Trp428) and also by favoring the association-prone conformation of mA-containing RNA in solution. The mA binding site dynamically equilibrates between multiple metastable conformations with four residues being involved in the regulation of mA binding (Trp428, Met438, Ser378, and Thr379). Trp428 switches between two conformational states to build and dismantle the aromatic cage. Interestingly, mutating Met438 and Ser378 to alanine does not alter mA binding to the protein but significantly redistributes the binding enthalpy and entropy terms, i.e., enthalpy-entropy compensation. Such compensation is reasoned by different entropy-enthalpy transduction associated with both conformational changes of the wild-type and mutant proteins and the redistribution of water molecules. In contrast, the point mutant Thr379Val significantly changes the thermal stability and binding capability of YTHDC1 to its natural ligand. Additionally, thermodynamic analysis and free energy calculations shed light on the role of a structural water molecule that synergistically binds to YTHDC1 with mA and acts as the hub of a hydrogen-bond network. Taken together, the experimental data and simulation results may accelerate the discovery of chemical probes, mA-editing tools, and drug candidates against reader proteins.
PubMed: 33472367
DOI: 10.1021/acs.jctc.0c01136
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.5 Å)
構造検証レポート
Validation report summary of 6zd8
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-30に公開中

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