View source for 9qfi


==Crystal structure of YTHDF2 in complex with compound 6 (AI-DF2-47)==
<StructureSection load='9qfi' size='340' side='right'caption='[[9qfi]], [[Resolution|resolution]] 1.91&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9qfi]] 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=9QFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9QFI FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.91&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1I5V:3-methyl-1~{H}-pyrazolo[3,4-d]pyrimidin-4-amine'>A1I5V</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=9qfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9qfi OCA], [https://pdbe.org/9qfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9qfi RCSB], [https://www.ebi.ac.uk/pdbsum/9qfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9qfi ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/YTHD2_HUMAN YTHD2_HUMAN] Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs. M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in the efficiency of mRNA splicing, processing and stability. Acts as a regulator of mRNA stability: binding to m6A-containing mRNAs results in the localization of to mRNA decay sites, such as processing bodies (P-bodies), leading to mRNA degradation.<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
N (6)-Adenosine methylation is the most abundant modification of mRNA. The three members of the YTH domain family proteins (YTHDF1-3) recognize in the cytoplasm the m(6)A-RNA modification. We screened a library of about 500,000 fragments (i.e., molecules with 11-20 non-hydrogen atoms) by docking into YTHDF2, which resulted in the identification of six active compounds among 47 tested in vitro (hit rate of 13%). The acquisition of 28 analogues of the docking hits provided an additional set of 10 active compounds (IC(50) &lt; 100 muM). Protein crystallography-guided optimization of a ligand-efficient fragment by the synthesis of 32 derivatives culminated in a series of YTHDF2 ligands, which show low-micromolar affinity measured by a fluorescence polarization (FP) assay and a homogeneous time-resolved fluorescence-based (HTRF) assay. The series is characterized by very favorable ligand efficiency (of about 0.3-0.4 kcal/mol per non-hydrogen atom). Compound 23 binds to YTHDF2 according to the FP and HTRF assays with a K (d) value of 1.3 muM and an IC(50) value of 11 muM, respectively, and it is selective against all of the other YTH reader proteins. Several compounds of the series bind to the three YTHDF proteins with similar low-micromolar affinity, while they are less potent for YTHDC1 and YTHDC2. In contrast, compounds 17 and 30 bind also to YTHDC2, with K (d) of 6.3 and 4.9 muM, respectively. We also disclose six crystal structures of YTHDF2 in the complex with the fragments identified by docking.

Discovery of YTHDF2 Ligands by Fragment-Based Design.,Invernizzi A, Nai F, Bedi RK, Vargas-Rosales PA, Li Y, Bochenkova E, Herok M, Zalesak F, Caflisch A ACS Bio Med Chem Au. 2025 Jun 27;5(4):753-765. doi: , 10.1021/acsbiomedchemau.5c00099. eCollection 2025 Aug 20. PMID:40860041<ref>PMID:40860041</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9qfi" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Caflisch A]]
[[Category: Invernizzi A]]
[[Category: Nai F]]