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6zcn

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Crystal structure of YTHDC1 with m6A

Structural highlights

6zcn is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

YTDC1_HUMAN RNA-binding protein that regulates alternative splice site selection.^[1]

Publication Abstract from PubMed

N6-Methyladenosine (m(6)A) 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 m(6)A 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 m(6)A 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 m(6)A-containing RNA in solution. The m(6)A binding site dynamically equilibrates between multiple metastable conformations with four residues being involved in the regulation of m(6)A 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 m(6)A 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 m(6)A 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, m(6)A-editing tools, and drug candidates against reader proteins.

Atomistic and Thermodynamic Analysis of N6-Methyladenosine (m(6)A) Recognition by the Reader Domain of YTHDC1.,Li Y, Bedi RK, Wiedmer L, Sun X, Huang D, Caflisch A J Chem Theory Comput. 2021 Feb 9;17(2):1240-1249. doi: 10.1021/acs.jctc.0c01136. , Epub 2021 Jan 20. PMID:33472367^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhang Z, Theler D, Kaminska KH, Hiller M, de la Grange P, Pudimat R, Rafalska I, Heinrich B, Bujnicki JM, Allain FH, Stamm S. The YTH domain is a novel RNA binding domain. J Biol Chem. 2010 May 7;285(19):14701-10. doi: 10.1074/jbc.M110.104711. Epub 2010, Feb 18. PMID:20167602 doi:http://dx.doi.org/10.1074/jbc.M110.104711
↑ Li Y, Bedi RK, 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. 2021 Feb 9;17(2):1240-1249. doi: 10.1021/acs.jctc.0c01136. , Epub 2021 Jan 20. PMID:33472367 doi:http://dx.doi.org/10.1021/acs.jctc.0c01136

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6zcn"

@@ Line 3: / Line 3: @@
 <StructureSection load='6zcn' size='340' side='right'caption='[[6zcn]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6zcn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZCN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZCN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6zcn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZCN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZCN FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6MZ:N6-METHYLADENOSINE-5-MONOPHOSPHATE'>6MZ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6MZ:N6-METHYLADENOSINE-5-MONOPHOSPHATE'>6MZ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zcn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zcn OCA], [https://pdbe.org/6zcn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zcn RCSB], [https://www.ebi.ac.uk/pdbsum/6zcn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zcn ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/YTDC1_HUMAN YTDC1_HUMAN]] RNA-binding protein that regulates alternative splice site selection.<ref>PMID:20167602</ref>
+[https://www.uniprot.org/uniprot/YTDC1_HUMAN YTDC1_HUMAN] RNA-binding protein that regulates alternative splice site selection.<ref>PMID:20167602</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bedi, R K]]
+[[Category: Bedi RK]]
-[[Category: Caflisch, A]]
+[[Category: Caflisch A]]
-[[Category: Huang, D]]
+[[Category: Huang D]]
-[[Category: Wiedmer, L]]
+[[Category: Wiedmer L]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: M6a]]
-[[Category: Rna binding protein]]
-[[Category: Ythdc1]]

6zcn

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Current revision

Crystal structure of YTHDC1 with m6A

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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