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7yyj

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Tetragonal crystal structure of YTHDF1 YTH domain (544AVV546 mutant)

Structural highlights

7yyj 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 2.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

YTHD1_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.^[1]

Publication Abstract from PubMed

Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the m(6)A mark on mRNA and represent valuable drug targets. Crystallographic structures have been determined for all three family members; however, discrepancies are present in the organization of the m(6)A-binding pocket. Here, we present new crystallographic structures of the YTH domain of YTHDF1, accompanied by computational studies, showing that this domain can exist in different stable conformations separated by a significant energetic barrier. During the transition, additional conformations are explored, with peculiar druggable pockets appearing and offering new opportunities for the design of YTH-interfering small molecules.

Pliability in the m(6)A-Binding Region Extends Druggability of YTH Domains.,Cazzanelli G, Dalle Vedove A, Spagnolli G, Terruzzi L, Colasurdo E, Boldrini A, Patsilinakos A, Sturlese M, Grottesi A, Biasini E, Provenzani A, Quattrone A, Lolli G J Chem Inf Model. 2024 Mar 11;64(5):1682-1690. doi: 10.1021/acs.jcim.4c00051. , Epub 2024 Feb 28. PMID:38417111^[2]

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

References

↑ Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27. PMID:24284625 doi:http://dx.doi.org/10.1038/nature12730
↑ Cazzanelli G, Dalle Vedove A, Spagnolli G, Terruzzi L, Colasurdo E, Boldrini A, Patsilinakos A, Sturlese M, Grottesi A, Biasini E, Provenzani A, Quattrone A, Lolli G. Pliability in the m(6)A-Binding Region Extends Druggability of YTH Domains. J Chem Inf Model. 2024 Mar 11;64(5):1682-1690. PMID:38417111 doi:10.1021/acs.jcim.4c00051